[{"projectId":"cf35915c-dd80-459b-b315-7354892c00c3","title":"Characterization of maternal and fetal immunity following in utero spina bifida repair and surgery-induced preterm birth","investigator":"Enninga, Elizabeth Ann","investigatorInstitution":"Mayo Clinic","publicationName":"","researchArea":"Other","prettyUrls":{"365":"martinez-2025-s"},"prettyUrlList":["martinez-2025-s"],"summary":"Fetal surgery (FS) for in utero spina bifida (SB) repair has demonstrated\nimproved survival and reduced morbidity for infants; however, preterm birth (PTB) is\nreported in 36-80% of cases following SB repair. This prospective cohort study enrolled pregnant participants across three medical centers between 2022-2023. The FS group underwent fetoscopic SB repair between 24-26 weeks of gestation. A control group of low-risk pregnancies without SB were also recruited and matched by parity, gestational age at surgery, and fetal sex. Maternal blood samples were collected at baseline (before FS) and two weeks post-surgery (POD14). T cell receptor sequencing was completed on these samples.","prettyUrl":"martinez-2025-s","following":false,"created":"05/16/2025","featured":false,"publishedDate":"05/20/2025","urlOrId":"martinez-2025-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1cec4c1b-17b8-4037-8314-bc7cf1ee7831","title":"ABab-A2 vs ABab-I Mice-TCRα repertoire","investigator":"Dhamodaran, Arunraj","investigatorInstitution":"T-knife GmbH/MDC Berlin, Present Address: Microbiome and Cancer Division, German Cancer Research Center in the Helmholtz Association (DKFZ), Heidelberg, Germany.","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"364":"dhamodaran-2025-nc1"},"prettyUrlList":["dhamodaran-2025-nc1"],"summary":"TBD","prettyUrl":"dhamodaran-2025-nc1","following":false,"created":"05/16/2025","featured":false,"publishedDate":"05/16/2025","urlOrId":"dhamodaran-2025-nc1","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3b68b71a-f58b-43ad-948e-133ea2dfc711","title":"ABab-A2 vs ABab-I Mice-TCRß repertoire","investigator":"Dhamodaran, Arunraj","investigatorInstitution":"Max Delbrück Center / T-knife GmbH, Present Address: Microbiome and Cancer Division, German Cancer Research Center in the Helmholtz Association (DKFZ), Heidelberg, Germany","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"363":"dhamodaran-2025-nc2"},"prettyUrlList":["dhamodaran-2025-nc2"],"summary":"TBD","prettyUrl":"dhamodaran-2025-nc2","following":false,"created":"05/16/2025","featured":false,"publishedDate":"05/16/2025","urlOrId":"dhamodaran-2025-nc2","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d3ad12ac-70db-4af0-8adc-0168dbb3ca4a","title":"γδ T-cell phenotype is impacted by CMV reactivation of patients short-term post-HSCT","investigator":"Uhlin, Michael","investigatorInstitution":"Department of Medicine, Huddinge, Karolinska Institutet","publicationName":"TBD","researchArea":"Other","prettyUrls":{"361":"hahn-2025-s"},"prettyUrlList":["hahn-2025-s"],"summary":"TBD","prettyUrl":"hahn-2025-s","following":false,"created":"05/16/2025","featured":false,"publishedDate":"05/16/2025","urlOrId":"hahn-2025-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"60246ee1-e0b5-40cd-a731-8dc42cbc02af","title":"The Molecular Epidemiology of Colorectal Cancer Study","investigator":"Gruber, Stephen B.","investigatorInstitution":"Department of Medical Oncology and Therapeutics Research","publicationName":"BMC Genomics","researchArea":"Cancer","prettyUrls":{"360":"schmit-2025-bmcg"},"prettyUrlList":["schmit-2025-bmcg"],"summary":"The Molecular Epidemiology of Colorectal Cancer Study (MECC) is a population-based study of incident CRC cases and healthy controls recruited from northern Israel from 1998 through 2017. After QC, 2,750 CRC cases with T cell receptor clonality and abundance data were derived from immunoSEQ assays.","prettyUrl":"schmit-2025-bmcg","following":false,"created":"05/08/2025","featured":false,"publishedDate":"05/15/2025","urlOrId":"schmit-2025-bmcg","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"db85fdb3-5a23-45ca-ba3d-499b9e64770d","title":"Locus folding mechanisms determine modes of antigen receptor gene assembly","investigator":"Bassing, Craig H.","investigatorInstitution":"Immunology Graduate Group, Perelman School of Medicine","publicationName":"JEM","researchArea":"Basic Immunology","prettyUrls":{"359":"allyn-2025-jem"},"prettyUrlList":["allyn-2025-jem"],"summary":"The dynamic folding of genomes regulates numerous biological processes, including antigen receptor (AgR) gene assembly. We show that, unlike other AgR loci, homotypic chromatin interactions and bidirectional chromosome looping both contribute to structuring Tcrb for efficient long-range V(D)J recombination. Inactivation of the CTCF binding element (CBE) or promoter at the most 5'Vβ segment (Trbv1) impaired loop extrusion originating locally and extending to DβJβ CBEs at the opposite end of Tcrb. Promoter or CBE mutation nearly eliminated Trbv1 contacts and decreased RAG endonuclease-mediated Trbv1 recombination. Importantly, Trbv1 rearrangement can proceed independent of substrate orientation, ruling out scanning by DβJβ-bound RAG as the sole mechanism of Vβ recombination, distinguishing it from Igh. Our data indicate that CBE-dependent generation of loops cooperates with promoter-mediated activation of chromatin to juxtapose Vβ and DβJβ segments for recombination through diffusion-based synapsis. Thus, the mechanisms that fold a genomic region can influence molecular processes occurring in that space, which may include recombination, repair, and transcriptional programming.","prettyUrl":"allyn-2025-jem","following":false,"created":"05/09/2025","featured":false,"publishedDate":"05/09/2025","urlOrId":"allyn-2025-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bd87e42c-4ad1-41dc-b375-c981d3527894","title":"Improving anti-CTLA-4 therapies through peptide masking and Fc non-fucosylation: preclinical characterization of three novel antibodies","investigator":"Jhatakia , Amy","investigatorInstitution":"Bristol Myers Squibb","publicationName":"TBD","researchArea":"Cancer Immunotherapy","prettyUrls":{"358":"jhatakia-2025-ccr"},"prettyUrlList":["jhatakia-2025-ccr"],"summary":"TBD","prettyUrl":"jhatakia-2025-ccr","following":false,"created":"04/15/2025","featured":false,"publishedDate":"04/15/2025","urlOrId":"jhatakia-2025-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e854ec7c-0b49-4d75-a4da-ada06977a456","title":"Sex Differences in B Cells from the Joints of Children with Oligoarticular Juvenile Idiopathic Arthritis","investigator":"Henderson, Lauren","investigatorInstitution":"Division of Immunology, Boston Children’s Hospital, Harvard Medical School","publicationName":"Arthritis and Rheumatology","researchArea":"Other","prettyUrls":{"357":"lam-2025-arj"},"prettyUrlList":["lam-2025-arj"],"summary":"TBD","prettyUrl":"lam-2025-arj","following":false,"created":"03/17/2025","featured":false,"publishedDate":"03/18/2025","urlOrId":"lam-2025-arj","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a69126b7-b916-42fb-b815-7bbd58e249b0","title":"Radical hemithorax radiotherapy induces an increase in circulating PD-1 + T lymphocytes and in the soluble levels of PD-L1 in Malignant Pleural Mesothelioma patients: a possible synergy with PD-1/PD-L1 targeting treatment?","investigator":"Muraro Elena","investigatorInstitution":"Centro di Riferimento Oncologico di Aviano (CRO), IRCCS - Immunopathology and Cancer Biomarkers Unit, Department of Translational Research","publicationName":"Frontiers in Immunology","researchArea":"Cancer Immunotherapy","prettyUrls":{"356":"revelant-2025-s"},"prettyUrlList":["revelant-2025-s"],"summary":"Malignant Pleural Mesothelioma (MPM) is an aggressive tumor associated with asbestos exposure, characterized by a poor prognosis, managed with surgery, chemotherapy and radiotherapy. Recently, immunotherapy gives a survival advantage compared to chemotherapy, but limited to the non-epithelioid histotype, the rarest type. Radical hemithorax radiotherapy (RHRT) improves the Overall Survival (OS) of MPM patients, irrespective of histotype, and is  able to induce immunomodulatory effects. In this study we aime to investigate changes in circulating T lymphocytes phenotype and activity, in MPM patients undergoing RHRT, to evaluate a possible therapeutic space for immunotherapy in this setting.\n\nTo assess immunomodulatory effects of RHRT we evaluate peripheral blood samples of 35 MPM patients collected before treatment, at the end of RT, and 1 month later. We first notice that higher Lymphocyte-to-Monocyte Ratio (LMR) levels, before RT, are  associated with an improved OS. The immune monitoring performed by ELISA assays reveals a significant increase in the serum levels of sPD‐L1 and IFN‐γ at the end of RHRT. Furthermore, the percentage of PD‐1+ cells, evaluated by flow cytometry, significantly raise  after RHRT in T cells, both CD4+ and CD8+. Also the proportion of proliferative cells is  significantly expanded after RHRT in all T cell subtypes. After treatment we observe  a significant increase in the number of patients showing WT-1 specific CD4+ T cells, measured by intracellular staining. The TCR repertoire analysis, investigated by Next Generation Sequencing, reveals an increased number of expanded T-cell clones after RHRT, and an association between TCR clonality and the percentage of proliferating cytotoxic T lymphocytes. The comparison of TCR sequences obtained in our cohort with those described in a literature cohort of MPM patients, reveals common entries, specific for MPM-associated antigens including WT-1.\n\nIn this setting, pre-treatment levels of LMR index seem to have a positive prognostic role, and RHRT would appear to induce immunomodulating effects, potential biomarkers for immunotherapy eligibility: i.e. increased PD-1+ T lymphocytes, proliferating T cells, expanded T cell clones and augmented levels of sPD-L1. These data  suggest the design of a prospective study evaluating a maintenance immunotherapy after RHRT in MPM, even in the epithelioid histotype.","prettyUrl":"revelant-2025-s","following":false,"created":"03/14/2025","featured":false,"publishedDate":"03/17/2025","urlOrId":"revelant-2025-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1a2afc0b-6b64-45d3-a370-7d84ab42ed68","title":"Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: A retrospective prognosis biomarker analysis","investigator":"Moreno, Victor","investigatorInstitution":"Catalan Institute of Oncology","publicationName":"PLOS Medicine","researchArea":"Cancer","prettyUrls":{"355":"sanz-pamplona-2025-plos"},"prettyUrlList":["sanz-pamplona-2025-plos"],"summary":"Background: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable.\nMethods and findings: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016).\nLimitations: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival.\nConclusion: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.","prettyUrl":"sanz-pamplona-2025-plos","following":false,"created":"02/27/2025","featured":false,"publishedDate":"03/01/2025","urlOrId":"sanz-pamplona-2025-plos","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c6f2c0bf-296a-4028-b5e6-3ee36f41de67","title":"Defining Resistance Mechanisms in TIL Therapy for NSCLC","investigator":"Creelan, Benjamin C.","investigatorInstitution":"Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute","publicationName":"TBD","researchArea":"Cancer","prettyUrls":{"353":"creelan-2025-s"},"prettyUrlList":["creelan-2025-s"],"summary":"TBD","prettyUrl":"creelan-2025-s","following":false,"created":"01/08/2025","featured":false,"publishedDate":"01/09/2025","urlOrId":"creelan-2025-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"190d24ea-d0ec-4296-b5d4-4cdff9ec7d59","title":"Graft-versus-host disease prophylaxis shapes T cell biology and immune reconstitution after hematopoietic cell transplant","investigator":"Kean, Leslie","investigatorInstitution":"Department of Pediatrics, Harvard Medical School, Division of Hematology/Oncology, Boston Children's Hospital, and Department of Pediatric Oncology, Dana-Farber Cancer Institute","publicationName":"TBD","researchArea":"Cellular Therapy","prettyUrls":{"352":"siegel-2024-nm"},"prettyUrlList":["siegel-2024-nm"],"summary":"Abstract: Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire,  underpinning post-transplant clinical outcomes.","prettyUrl":"siegel-2024-nm","following":false,"created":"12/23/2024","featured":false,"publishedDate":"12/27/2024","urlOrId":"siegel-2024-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8378f7d6-196a-46b6-89d2-5fcf21a3baa7","title":"Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models","investigator":"Pierini, Stefano","investigatorInstitution":"Carisma Therapeutics","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"351":"peirini-2024-nc"},"prettyUrlList":["peirini-2024-nc"],"summary":"We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors","prettyUrl":"peirini-2024-nc","following":false,"created":"12/13/2024","featured":false,"publishedDate":"12/13/2024","urlOrId":"peirini-2024-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2439ae7e-5c9c-4149-8c9f-8ff65ec0db7d","title":"Pre-Transplant T-Cell Clonal Analysis Identifies CD8+ Donor Reactive Clones That Contribute To Kidney Transplant Rejection Following Two Different Induction Modalities","investigator":"Mathew, James","investigatorInstitution":"Northwestern Universty Feinberg School of Medicine","publicationName":"Frontiers in Immunology","researchArea":"Organ transplant","prettyUrls":{"350":"sanders-2024-stm"},"prettyUrlList":["sanders-2024-stm"],"summary":"Introduction: Responses to allogeneic human leukocyte antigen (HLA) molecules limit the survival of transplanted organs. The changes in T-cell alloreactivity that contribute to this process, however, are not fully understood. We defined a set of donor reactive T-cell clones (DRTC) with the goal to elucidate signatures of kidney allograft rejection.\n\nMethods: DRTC were identified pretransplant using an anti-donor mixed lymphocyte reaction assay: CFSE-diluting CD4+ and CD8+ DRTC were flow-sorted, and the TCR sequences were identified using Adaptive Immunosequencing. DRTC were then tracked in post-transplant biopsies, blood, and urine samples in a cohort of kidney transplant recipients. \n\nResults: In patients with an abnormal biopsy, the majority of CD8+ DRTC found within the allograft were detected in the circulating pre-transplant repertoire. Circulating CD8+ DRTC were more abundant pre- and post-transplant in patients that received non-lymphodepletional induction and developed an abnormal biopsy when compared to stable patients. Additionally, DRTC were detected as early as two weeks post-transplant in the urine of some patients, with some of these clones subsequently identified in follow-up kidney biopsy samples.\n\nDiscussion: The findings of our study add to our understanding of T-cell alloreactivity following kidney transplantation and provide evidence for the role of pre-defined alloreactive T-cells in the development of allograft rejection.","prettyUrl":"sanders-2024-stm","following":false,"created":"08/13/2024","featured":false,"publishedDate":"12/06/2024","urlOrId":"sanders-2024-stm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"0f19e35e-fedd-4157-9ea4-cccd7cfefc7d","title":"Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma","investigator":"Hogg, Graham","investigatorInstitution":"Washington University School of Medicine in St. Louis","publicationName":"Oncoimmunology","researchArea":"Cancer","prettyUrls":{"349":"pothuri-2024-oi"},"prettyUrlList":["pothuri-2024-oi"],"summary":"Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and “True entropy.” Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.","prettyUrl":"pothuri-2024-oi","following":false,"created":"11/13/2024","featured":false,"publishedDate":"11/19/2024","urlOrId":"pothuri-2024-oi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6f9fb8df-7215-47fc-9d54-7f52d973b8ee","title":"TBD","investigator":"Elyanow, Rebecca","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"TBD","researchArea":"Autoimmune Disorders","prettyUrls":{"348":"elyanow-2024-s"},"prettyUrlList":["elyanow-2024-s"],"summary":"TBD","prettyUrl":"elyanow-2024-s","following":false,"created":"11/05/2024","featured":false,"publishedDate":"11/07/2024","urlOrId":"elyanow-2024-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d300d36c-2166-4525-b45b-95085e1149f1","title":"Clonal analysis of SepSecS-specific B and T cells in autoimmune hepatitis","investigator":"Sallusto, Federica","investigatorInstitution":"Institute for Research in Biomedicine (IRB)","publicationName":"Journal of Clinical Investigation","researchArea":"Autoimmune Disorders","prettyUrls":{"347":"kramer-2024-jci"},"prettyUrlList":["kramer-2024-jci"],"summary":"TBD","prettyUrl":"kramer-2024-jci","following":false,"created":"10/29/2024","featured":false,"publishedDate":"10/29/2024","urlOrId":"kramer-2024-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4f73c166-de99-439a-9594-1bd1b0e699ce","title":"Tumor-resident Lactobacillus iners confers chemoradiation resistance through lactate-induced metabolic rewiring","investigator":"Colbert, Lauren E.","investigatorInstitution":"The University of Texas M.D. Anderson Cancer Center","publicationName":"Cancer Cell","researchArea":"Cancer","prettyUrls":{"346":"colbert-2024-cc"},"prettyUrlList":["colbert-2024-cc"],"summary":"Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in cervical cancer patients through a combined approach of deep microbiome sequencing, sequential, targeted bacterial culture and in vitro assays. We identify that an obligate L-lactate producing lactic acid bacteria found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring of tumors. Genomically similar L-lactate producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal cancer, lung cancer, head and neck cancer and skin cancer. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways to cause therapy resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.","prettyUrl":"colbert-2024-cc","following":false,"created":"10/22/2024","featured":false,"publishedDate":"10/22/2024","urlOrId":"colbert-2024-cc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"63145368-9b39-4cd1-b9bf-88e3eb7396cf","title":"A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer","investigator":"West, Emma","investigatorInstitution":"Leeds Institute of Medical Research at St. James’s, Translational Cancer Immunotherapy Group","publicationName":"TBD","researchArea":"Cancer Immunotherapy","prettyUrls":{"345":"west-2024-s"},"prettyUrlList":["west-2024-s"],"summary":"Background: Effective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favorable clinical outcomes.  Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoural administration routes.  \nMethods: We conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine to fifteen mCRC patients.  \nResults: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by virus within tumour biopsies.  Functional transcription of the FCU1 transgene indicates viral replication within the tumour, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002.  IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death.  Gene Ontology analyses of differentially-expressed genes reveal a significant immune response at the transcriptional level in response to treatment.  Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer- and neo-antigens, with elevated functional activity, may be associated with improved anti-cancer activity. Despite these findings, no clinical efficacy was observed. \nConclusions: In summary, these data demonstrate delivery of OV to tumour via IHA administration, associated with viral replication and significant peripheral immune activation.  Collectively, the data supports the need for future studies using IHA administration of OVs.","prettyUrl":"west-2024-s","following":false,"created":"10/16/2024","featured":false,"publishedDate":"10/16/2024","urlOrId":"west-2024-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"30f6e6c6-cdee-4d15-abeb-81ff75813086","title":"IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8+ T cells","investigator":"Duhen, Thomas","investigatorInstitution":"Earle A. Chiles Research Institute, Providence Cancer Institute","publicationName":"TBD","researchArea":"Cancer Immunotherapy","prettyUrls":{"344":"fesneau-2024-nc"},"prettyUrlList":["fesneau-2024-nc"],"summary":"Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8+ T cells in the anti-tumor response and the regulation of NKG2A expression are still poorly understood. Here, by performing CITE-seq on human T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced in tumor-infiltrating  CD8+ T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) T cells. This developmental trajectory lead to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of the NKG2A on naïve CD8+ T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation and increased TGF-β levels. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8+ T cells exposed to a TGF-b-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.","prettyUrl":"fesneau-2024-nc","following":false,"created":"10/07/2024","featured":false,"publishedDate":"10/07/2024","urlOrId":"fesneau-2024-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8fe07a3e-a1a4-4b06-8481-b909a1b9c1c8","title":"Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer","investigator":"Sears, Rosalie C.","investigatorInstitution":"Department of Molecular and Medical Genetics, Oregon Health and Science University","publicationName":"Nature Cancer","researchArea":"Cancer","prettyUrls":{"343":"link-2023-nc"},"prettyUrlList":["link-2023-nc"],"summary":"Metastatic pancreatic ductal adenocarcinoma (mPDAC) is lethal, yet a subset of patients who have metastatic disease that spreads to the lung, but not the liver, survive longer. We generated large genomic, transcriptomic and T cell receptor sequencing datasets, along with deep clinical annotation, to elucidate unique tumor and immune features that distinguish patients who develop metastases in the liver (liver cohort) versus those with lung-avid but liver-averse mPDAC (lung cohort). Lung cohort patients had better survival outcomes than liver cohort patients even within the same tumor subtype. Using a novel gene signature for liver versus lung organotropism in primary tumors independent from known tumor subtypes (pORG), we identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors and greater density of leukocytes in low pORG/lung cohort tumors. Patients with low pORG tumors survived longer, especially if their tumors had alterations in DNA damage repair genes. Patients that are in the lung cohort demonstrated new T cell clonal development in their primary and metastatic tumors leading to diverse peripheral blood TCR repertoires. Our study demonstrates that liver-avid metastatic PDAC is associated with an ongoing RS response, whereas tumors lacking the RS response with ongoing T cell clonal responses may have unique vulnerabilities allowing long-term survival in patients with lung-avid, liver-averse metastatic PDAC.","prettyUrl":"link-2023-nc","following":false,"created":"02/08/2023","featured":false,"publishedDate":"09/24/2024","urlOrId":"link-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7d481cd7-1cf4-4612-8cbd-b33b333ccfd9","title":"Neoadjuvant or concurrent Anti PD-L1 (Atezolizumab) with chemoradiation for locally advanced cervical cancer","investigator":"Zamarin, Dmitriy","investigatorInstitution":"Icahn School of Medicine at Mount Sinai","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"340":"mayadev-2024-nc"},"prettyUrlList":["mayadev-2024-nc"],"summary":"Combination of immune checkpoint blockade (ICB) with chemoradiation (CRT) is now approved in patients with locally advanced cervical cancer (LACC) but optimal sequencing of CRT and ICB is unknown. NRG-GY017 (NCT03738228) was a randomized phase I trial of differential sequencing of atezolizumab and CRT in patients with high-risk node-positive LACC. The primary objective was to evaluate the expansion of tumor-associated T-cell receptor (TCR) clones in peripheral blood as a surrogate measure of anti-tumor immune response. Secondary objectives included toxicity and 2-year disease-free survival (DFS). Forty patients were randomized and 36 received 3 doses of atezolizumab neoadjuvant and concurrent with CRT (Arm A) vs. concurrent with CRT (Arm B). After cycle 1, there was peripheral expansion of higher proportion of tumor-associated TCR clones in Arm A than in Arm B (median 0.39 vs. 0.06, p=0.0025) that remained numerically higher at the day 21 primary endpoint (p=0.052 by 2-sample t test). At the median follow up of 25.8 months, 2-year DFS was 76% in Arm A and 56% in Arm B (p=0.28). There were no new safety signals. In conclusion, addition of neoadjuvant ICB prior to CRT was safe and was associated with immunologically and clinically favorable outcomes, warranting larger confirmatory studies.","prettyUrl":"mayadev-2024-nc","following":false,"created":"09/16/2024","featured":false,"publishedDate":"09/16/2024","urlOrId":"mayadev-2024-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8ddebffc-242e-48e2-a84c-9c8ec6584e89","title":"Late-stage tertiary lymphoid structures in hepatocellular carcinoma treated with neoadjuvant immune checkpoint blockade","investigator":"Shu, Daniel","investigatorInstitution":"University of Maryland","publicationName":"TBD","researchArea":"Cancer Immunotherapy","prettyUrls":{"339":"shu-2024-ni"},"prettyUrlList":["shu-2024-ni"],"summary":"Coming soon","prettyUrl":"shu-2024-ni","following":false,"created":"09/09/2024","featured":false,"publishedDate":"09/10/2024","urlOrId":"shu-2024-ni","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1b8516df-d9ad-49f4-ac56-a661e6456830","title":"AVATAR mice for personalized medicine in patients with atopic dermatitis","investigator":"Kim, Hye Li","investigatorInstitution":"Yonsei university","publicationName":"TBD","researchArea":"Other","prettyUrls":{"338":"park-2024-s"},"prettyUrlList":["park-2024-s"],"summary":"TBD","prettyUrl":"park-2024-s","following":false,"created":"09/06/2024","featured":false,"publishedDate":"09/06/2024","urlOrId":"park-2024-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"945aadf7-e2ad-4a79-93b7-f013f9d9ba1b","title":"Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection","investigator":"Sircy, Linda","investigatorInstitution":"University of Utah","publicationName":"TBD","researchArea":"Other","prettyUrls":{"337":"williams-2024-p"},"prettyUrlList":["williams-2024-p"],"summary":"Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection or immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.","prettyUrl":"williams-2024-p","following":false,"created":"08/27/2024","featured":false,"publishedDate":"08/28/2024","urlOrId":"williams-2024-p","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"362fe554-59cd-469e-81d1-c87768ef434d","title":"Phase 1 study combining elotuzumab with autologous stem cell transplant and lenalidomide for multiple myeloma","investigator":"Kim-schulze, Seunghee","investigatorInstitution":"The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mt. Sinai","publicationName":"Journal for ImmunoTherapy of Cancer","researchArea":"Cancer","prettyUrls":{"335":"coffey-2024-jitc"},"prettyUrlList":["coffey-2024-jitc"],"summary":"Background: Autologous stem cell transplantation (ASCT) after induction therapy improves disease-free survival for patients with multiple myeloma (MM). While the goal of ASCT is to render a minimal disease state, it is also associated with eradication of immunosuppressive cells, and we hypothesize that early introduction of immunotherapy post-ASCT may provide a window of opportunity to boost treatment efficacy.\n\nMethods: We conducted a phase 1 clinical trial to investigate the application of autologous lymphocyte infusion and anti-SLAMF7 monoclonal antibody, elotuzumab, after ASCT in patients with newly diagnosed MM previously treated with induction therapy. In addition to CD34+ stem cells, peripheral blood mononuclear cells were harvested prior to transplant and infused on day 3 after stem cell infusion to accelerate immune reconstitution and provide autologous natural killer (NK) cells that are essential to the mechanism of elotuzumab. Elotuzumab was administered starting on day 4 and then every 28 days after until 1 year post-ASCT. Cycles 4–12 were administered with standard-of-care lenalidomide maintenance.\n\nResults: All subjects were evaluated for safety, and 13 of 15 subjects completed the treatment protocol. At 1 year post-ASCT, the disease status of enrolled subjects was as follows: five stringent complete responses, one complete response, six very good partial responses, one partial response, and two progressive diseases. The treatment plan was well tolerated, with most grade 3 and 4 AEs being expected hematologic toxicities associated with ASCT. Correlative analysis of the immune microenvironment demonstrated a trend toward reduced regulatory T cells during the first 3 months post-transplant followed by an increase in NK cells and monocytes in patients achieving a complete remission.\n\nConclusions: This phase 1 clinical trial demonstrates that early introduction of immunotherapy after ASCT is well tolerated and shows promising disease control in patients with MM, accompanied by favorable changes in the immune microenvironment.","prettyUrl":"coffey-2024-jitc","following":false,"created":"08/12/2024","featured":false,"publishedDate":"08/12/2024","urlOrId":"coffey-2024-jitc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"737666e5-ffcf-4e0e-b51a-30ff5ad34405","title":"Xenogeneic Graft-Versus-Host Disease in Humanized NSG and NSG-HLA-A2/HHD Mice","investigator":"Ehx, Gregory","investigatorInstitution":"GIGA Institute: Hematology","publicationName":"Frontiers in Immunology","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"334":"ehx-2024-ji"},"prettyUrlList":["ehx-2024-ji"],"summary":"Despite the increasing use of humanized mouse models to study new approaches of graft-versus-host disease (GVHD) prevention, the pathogenesis of xenogeneic GVHD (xGVHD) in these models remains misunderstood. The aim of this study is to describe this pathogenesis in NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice infused with human PBMCs and to assess the impact of the expression of HLA-A0201 by NSG mice cells (NSG-HLA-A2/HHD mice) on xGVHD and graft-versus-leukemia (GvL) effects, by taking advantage of next-generation technologies. We found that T cells recovered from NSG mice after transplantation had upregulated expression of genes involved in cell proliferation, as well as in TCR, co-stimulatory, IL-2/STAT5, mTOR and Aurora kinase A pathways. T cells had mainly an effector memory or an effector phenotype and exhibited a Th1/Tc1-skewed differentiation. TCRβ repertoire diversity was markedly lower both in the spleen and lungs (a xGVHD target organ) than at infusion. There was no correlation between the frequencies of specific clonotypes at baseline and in transplanted mice. Finally, expression of HLA-A0201 by NSG mice led to more severe xGVHD and enhanced GvL effects toward HLA-A2+ leukemic cells. Altogether our data demonstrate that the pathogenesis of xGVHD shares important features with human GVHD and that NSG-HLA-A2/HHD mice could serve as better model to study GVHD and GvL effects.","prettyUrl":"ehx-2024-ji","following":false,"created":"07/23/2024","featured":false,"publishedDate":"07/24/2024","urlOrId":"ehx-2024-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"eaa3e269-ee08-4a6b-965a-50f228cdc2a4","title":"IL-7-dependent and -independent lineages of IL-7R-dependent human T cells","investigator":"Puel, A","investigatorInstitution":"Institut IMAGINE","publicationName":"Journal of Clinical Investigation","researchArea":"Basic Immunology","prettyUrls":{"333":"arango-franco-2024-jci"},"prettyUrlList":["arango-franco-2024-jci"],"summary":"TBD","prettyUrl":"arango-franco-2024-jci","following":false,"created":"06/19/2024","featured":false,"publishedDate":"06/21/2024","urlOrId":"arango-franco-2024-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"394ed703-0279-4982-8213-e2dbbc12c136","title":"COVID-19 vaccinated Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia show Spike reactive antibodies and multifunctional T-cells","investigator":"Parekh, Chintan","investigatorInstitution":"Children's Hospital Los Angeles","publicationName":"TBD","researchArea":"Vaccine efficacy","prettyUrls":{"332":"parker-2024-s"},"prettyUrlList":["parker-2024-s"],"summary":"Little is known about the efficacy of COVID-19 vaccines during acute lymphoblastic leukemia therapy (ALL); data for COVID-19 vaccine immune responses in pediatric leukemia remain sparse. We used flow cytometry and TCR sequencing to assess Spike Reactive T-cell responses in 20 patients aged 5-25 years undergoing Acute lymphoblastic leukemia (ALL) chemotherapy who had received COVID-19 vaccination. TCR sequencing was also done on T-cells from 5 COVID-19 vaccinated healthy adult individuals (healthy controls). Spike reactive T-cells (SRT) were detected by flow cytometry in 9 of 20 (45%) vaccinated patients undergoing ALL chemotherapy. Sequencing revealed public CD4+ and CD8+ TCR sequences reactive to epitopes across the Spike Protein in these patients. In conclusion, COVID-19 vaccination induced T-cell responses in a substantial fraction of children and young adults undergoing ALL chemotherapy.","prettyUrl":"parker-2024-s","following":false,"created":"06/07/2024","featured":false,"publishedDate":"06/10/2024","urlOrId":"parker-2024-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fc8472cd-aebc-4b40-b8e7-37f47a9b170f","title":"Expansion of the tissue-based T-cell receptor repertoire is distinct from the PBMC response after immunotherapeutic HSV-2 vaccine","investigator":"Ford, Emily S","investigatorInstitution":"Vaccine and Infectious Diseases Division and Division of Allergy and Infectious Diseases","publicationName":"TBD","researchArea":"Response to Therapeutic Agent","prettyUrls":{"331":"ford-2024-jci"},"prettyUrlList":["ford-2024-jci"],"summary":"Coming Soon...","prettyUrl":"ford-2024-jci","following":false,"created":"06/06/2024","featured":false,"publishedDate":"06/10/2024","urlOrId":"ford-2024-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"98c4a4eb-fa62-48d5-8637-170f0a86b0ab","title":"Differential tumor immune microenvironment coupled with tumor progression or tumor eradication in HPV-antigen expressing squamous cell carcinoma (SCC) models.","investigator":"Wang, Jing","investigatorInstitution":"Department of Medicine, University of Pittsburgh","publicationName":"Frontiers in Immunology","researchArea":"Cancer","prettyUrls":{"330":"shivarudrappa-2024-fi"},"prettyUrlList":["shivarudrappa-2024-fi"],"summary":"Human papilloma virus (HPV) is an etiological factor of head and neck squamous cell carcinoma (HNSCC).  To investigate the role of HPV antigen in anti-tumor immunity, we established mouse models by expressing HPV16 E6 and E7 in a SCC tumor cell line.  We obtained two HPV antigen-expressing clones (C-225 and C-100) transplantable into C57BL/6 recipients.  We found that C-225 elicited complete eradication in C57BL/6 mice (eradicated), whereas C-100 grew progressively (growing).  We examined immune tumor microenvironment (TME) using flow cytometry and found that eradicated or growing tumors exhibited differential immune profiles that may influence the outcome of anti-tumor immunity.  Surprisingly, the percentage of CD8 and CD4 tumor-infiltrating lymphocytes (TILs) was much higher in growing (C-100) than eradicated (C-225) tumor. However, the TILs upregulated PD-1 and LAG-3 more potently and exhibited impaired effector functions in growing tumor compared to their counterparts in eradicated tumor.  C-225 TME is highly enriched with myeloid cells, especially polymorphonuclear (PMN) myeloid-derived suppressor cells (MDSC), whereas the percentage of M-MDSC and tumor-associated macrophages (TAMs) was much higher in C-100 TME, especially M2-TAMs (CD206+). The complete eradication of C-225 depended on CD8 T cells and elicited anti-tumor memory responses upon secondary tumor challenge. We employed DNA sequencing to identify differences in the T cell receptor of peripheral blood lymphocytes pre- and post-secondary tumor challenge. Lastly, C-225 and C-100 tumor lines harbored different somatic mutations.  Overall, we uncovered differential immune TME that may underlie the divergent outcomes of anti-tumor immunity by establishing two SCC tumor lines, both of which express HPV16 E6 and E7 antigens. Our experimental models may provide a platform for pinpointing tumor-intrinsic versus host-intrinsic differences in orchestrating an immunosuppressive TME in HNSCCs and for identifying new targets that render tumor cells vulnerable to immune attack.","prettyUrl":"shivarudrappa-2024-fi","following":false,"created":"06/04/2024","featured":false,"publishedDate":"06/04/2024","urlOrId":"shivarudrappa-2024-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c5a35918-da0a-49fd-8ec5-8c022554aeca","title":"IgH and IgL data for MRD tracking post-CD20 CAR T cell therapy in a patient with mantle cell lymphoma","investigator":"Till, Brian","investigatorInstitution":"Fred Hutchinson Cancer Center","publicationName":"Blood Cancer Discovery","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"329":"mo-2024-3-bcd"},"prettyUrlList":["mo-2024-3-bcd"],"summary":"A 62 year old man with mantle cell lymphoma was treated with cyclophosphamide (CY) lymphodepletion, 3 escalating doses of CD20-targeted CAR T cell infusions, and IL-2 injections as per Till et al, Blood 2012;  119(17):3940-50. He was re-treated with CY, CAR-T (1 dose only) and IL-2 after relapse 2 years later, had transient apparent progression at 6 weeks post CAR-T infusion, followed by a remission a few weeks later, and remained in remission for several years. These samples provide data for MRD tracking. The samples are as follows:\n\n02583-01OH-207791: Tumor biopsy from 48h post his 3rd CAR-T infusion (IGH)\n02583-01OL-207791: Tumor biopsy from 48h post his 3rd CAR-T infusion (IGL)\n02583-02BH: Baseline #2 (before re-treatment with 4th CAR T cell infusion) (IGH)\n02583-02BL: Baseline #2 (before re-treatment with 4th CAR T cell infusion) (IGH)\n02583-03BH-1: 1.7 months post the 4th CAR-T infusion (IGH)\n02583-03BL-1: 1.7 months post the 4th CAR-T infusion (IGL)\n02583-03BH: 6.4 months post the 4th CAR-T infusion (IGH)\n02583-03BL: 6.4 months post the 4th CAR-T infusion (IGL)\n02583-05BH:  64 months post the 4th CAR-T infusion (IGH)\n02583-05BL: 64 months post the 4th CAR-T infusion (IGL)","prettyUrl":"mo-2024-3-bcd","following":false,"created":"05/03/2024","featured":false,"publishedDate":"05/07/2024","urlOrId":"mo-2024-3-bcd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"859cc661-77b7-4900-9671-c7d673c8ba30","title":"B cell clonality data over time post-CD20 CAR-T in a follicular lymphoma patient with late remission","investigator":"Till, Brian","investigatorInstitution":"Fred Hutchinson Cancer Center","publicationName":"Blood Cancer Discovery","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"328":"mo-2024-2-bcd"},"prettyUrlList":["mo-2024-2-bcd"],"summary":"A 28 year-old patient was treated with cyclophosphamide lymphodepletion, 3 escalating doses of CD20-targeted CAR T cells (as per Till et al, Blood 2012; 119(17):3940-50), with a delayed partial response around 3 months and then a complete response around 2.5 years, suggesting an endogenous anti-tumor response. This project contains the IgH and IgK data from his tumor biopsy and at baseline and at 3 years, demonstrating resolution of two prominent subclones but residual levels of one subclone (MRD) at 3 years post-treatment.","prettyUrl":"mo-2024-2-bcd","following":false,"created":"05/03/2024","featured":false,"publishedDate":"05/07/2024","urlOrId":"mo-2024-2-bcd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"05fbfd79-e689-43b3-97cc-2d63547ebf4d","title":"TCR-beta repertoire over time post-CD20 CAR-T in a follicular lymphoma patient with late remission","investigator":"Till, Brian","investigatorInstitution":"Fred Hutchinson Cancer Center","publicationName":"Blood Cancer Discovery","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"327":"mo-2024-1-bcd"},"prettyUrlList":["mo-2024-1-bcd"],"summary":"A 28 year-old patient was treated with cyclophosphamide lymphodepletion, 3 escalating doses of CD20-targeted CAR T cells (as per Till et al, Blood 2012; 119(17):3940-50), with a delayed partial response around 3 months and then a complete response around 2.5 years, suggesting an endogenous anti-tumor response.","prettyUrl":"mo-2024-1-bcd","following":false,"created":"05/03/2024","featured":false,"publishedDate":"05/07/2024","urlOrId":"mo-2024-1-bcd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"0518c8a6-b11d-4865-97f9-49906f557723","title":"CLN-617 retains IL-2 and IL-12 in injected tumors to drive robust and systemic immune-mediated anti-tumor activity","investigator":"Rakhra, Kavya","investigatorInstitution":"Cullinan Oncology","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"326":"mehta-2024-cir"},"prettyUrlList":["mehta-2024-cir"],"summary":"Despite clinical evidence of anti-tumor activity, cytokine therapies have been hampered by a narrow therapeutic window and limited response rate. Two such cytokines are interleukin 2 (IL-2) and interleukin 12 (IL-12), which potently synergize to activate and proliferate T cells and natural killer (NK) cells. However, the only approved human IL-2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL-12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL-2 and IL-12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL-2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL-12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. IT administration of a murine surrogate of CLN-617, mCLN-617, eradicates established treated and untreated tumors in syngeneic models, synergizes with anti-PD1 therapy, and generates a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).","prettyUrl":"mehta-2024-cir","following":false,"created":"04/02/2024","featured":false,"publishedDate":"04/03/2024","urlOrId":"mehta-2024-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4cc41219-0c45-4db4-afc2-b7266b16855b","title":"Third-Party Cytotoxic T Lymphocytes for High-Risk Patients with Covid-19","investigator":"Grosso, Dolores","investigatorInstitution":"Thomas Jefferson University Sidney Kimmel Cancer Center, Department of Medical Oncology","publicationName":"TBD","researchArea":"Infectious Disease","prettyUrls":{"325":"grosso-2023-nc"},"prettyUrlList":["grosso-2023-nc"],"summary":"Treatment with off-the-shelf cellular therapy may provide direct and rapid treatment for COVID-19, overcoming the delayed adaptive immune responses associated with poor outcomes in high-risk patients. Thirty ambulatory patients with COVID-19 were enrolled on a phase I trial to assess the safety of 3rd party, COVID-19-specific cytotoxic T lymphocytes (CTLs). Twelve “Interventional” patients matching the HLA-A*02:01 restriction of the CTLs received a single infusion of one of four escalating doses of a product containing 68.5% COVID-19-specific CD8+ CTLs/total cells. Eighteen “Observational” patients lacking HLA-A*02:01 served as comparisons. No dose-limiting toxicities were observed. Nasal swab PCR data showed ≥ 88% viral elimination in 92% of patients in 4 days and the CTLs remained detectable at 6 months. Interventional patients consistently reported symptomatic improvement 2-3 days after infusion, whereas improvement was more variable in Observational patients. Our study shows that COVID-19-specific CTLs are a potentially useful cellular therapy for COVID-19.","prettyUrl":"grosso-2023-nc","following":false,"created":"03/26/2024","featured":false,"publishedDate":"03/26/2024","urlOrId":"grosso-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"0a424f8e-c83e-463e-9beb-a38c3db17ffe","title":"Personalized Neoantigen Vaccine and Pembrolizumab in Advanced Hepatocellular Carcinoma: A phase 1/2 trial","investigator":"Yarchoan, Mark","investigatorInstitution":"Bloomberg–Kimmel Institute for Cancer Immunotherapy. Johns Hopkins University School of Medicine","publicationName":"Nature Medicine","researchArea":"Cancer","prettyUrls":{"323":"yarchoan-2024-nm"},"prettyUrlList":["yarchoan-2024-nm"],"summary":"PD-1 inhibitors have modest efficacy as monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results of a single-arm, open-label, phase 1/2 study (NCT04251117) of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens co-administered with plasmid-encoded IL-12, plus pembrolizumab, in advanced HCC patients previously treated with a multi-tyrosine kinase inhibitor (mTKI). The most common treatment-related adverse events were injection site reactions, observed in 41.6% (15/36) of patient. No dose-limiting toxicities or treatment-related grade ³3 events were observed. ORR (mITT) per RECIST 1.1 was 30.6% (11/36) with 8.3% (3/36) of patients achieving a complete response (CR). Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19/22 (86.4%) evaluable patients by ELISpot. Multi-parametric cellular profiling revealed active, proliferative, and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. In 14/14 (100%) of patients with paired pre- and on-treatment blood and tumor biopsies, we identified by TCRβ bulk sequencing expanded T cells clones in the peripheral blood that also trafficked into the tumor. Single-cell analysis revealed post-treatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity determining region (CDR) cloning of expanded T cell clones in the tumors post-vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV mechanism of action based on the induction of anti-tumor T cells, and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC.","prettyUrl":"yarchoan-2024-nm","following":false,"created":"02/07/2024","featured":false,"publishedDate":"03/19/2024","urlOrId":"yarchoan-2024-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3deb5a1d-35ec-4499-840d-629b176571e1","title":"COGNATE ANTIGEN ENGAGEMENT INDUCES HIV-1 EXPRESSION IN CD4+ T CELLS FROM PEOPLE ON LONG-TERM ART","investigator":"Simonetti, F","investigatorInstitution":"Johns Hopkins University, School of Medicine","publicationName":"TBD","researchArea":"HIV","prettyUrls":{"322":"moskovljevic_2024_s"},"prettyUrlList":["moskovljevic_2024_s"],"summary":"TBD","prettyUrl":"moskovljevic_2024_s","following":false,"created":"03/07/2024","featured":false,"publishedDate":"03/07/2024","urlOrId":"moskovljevic_2024_s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"164cfc6a-82bb-4cca-998c-a02ce967c44d","title":"Identification of apolipoprotein B–reactive CDR3 motifs allows tracking of atherosclerosis-related memory CD4+T cells in multiple donors","investigator":"Ley, Klaus","investigatorInstitution":"Immunology Center of Georgia","publicationName":"Frontiers in Immunology","researchArea":"Other","prettyUrls":{"321":"roy-2024-fi"},"prettyUrlList":["roy-2024-fi"],"summary":"Introduction: Atherosclerosis is a major pathological condition that underlies many cardiovascular diseases (CVDs). Its etiology involves breach of tolerance to self, leading to clonal expansion of autoreactive apolipoprotein B (APOB)–reactive CD4+T cells that correlates with clinical CVD. The T-cell receptor (TCR) sequences that mediate activation of APOB-specific CD4+T cells are unknown.\nMethods: In a previous study, we had profiled the hypervariable complementarity determining region 3 (CDR3) of CD4+T cells that respond to six immunodominant APOB epitopes in most donors. Here, we comprehensively analyze this dataset of 149,065 APOB-reactive and 199,211 non-reactive control CDR3s from six human leukocyte antigen–typed donors.\nResults: We identified 672 highly expanded (frequency threshold > 1.39E-03) clones that were significantly enriched in the APOB-reactive group as compared to the controls (log10 odds ratio ≥1, Fisher’s test p < 0.01). Analysis of 114,755 naïve, 91,001 central memory (TCM) and 29,839 effector memory (TEM) CDR3 sequences from the same donors revealed that APOB+ clones can be traced to the complex repertoire of unenriched blood T cells. The fraction of APOB+ clones that overlapped with memory CDR3s ranged from 2.2% to 46% (average 16.4%). This was significantly higher than their overlap with the naïve pool, which ranged from 0.7% to 2% (average 1.36%). CDR3 motif analysis with the machine learning–based\nin-silico tool, GLIPHs (grouping of lymphocyte interactions by paratope hotspots), identified 532 APOB+ motifs. Analysis of naïve and memory CDR3 sequences with GLIPH revealed that ~40% (209 of 532) of these APOB+motifs were enriched in the memory pool. Network analysis with Cytoscape revealed extensive sharing of the\nmemory-affiliated APOB+ motifs across multiple donors. We identified six motifs that were present in TCM and TEM CDR3 sequences from >80% of the donors and were highly enriched in the APOB-reactive TCR repertoire.\nDiscussion: The identified APOB-reactive expanded CD4+T cell clones and conserved motifs can be used to annotate and track human atherosclerosis-related autoreactive CD4+T cells and measure their clonal expansion.","prettyUrl":"roy-2024-fi","following":false,"created":"03/07/2024","featured":false,"publishedDate":"03/07/2024","urlOrId":"roy-2024-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d1877678-b683-4b19-bacd-dcb68ae2af2c","title":"A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron","investigator":"Sharma, G","investigatorInstitution":"Pohang University of Science and Technology (POSTECH), Immunobiome Inc.","publicationName":"Nature Immunology","researchArea":"Other","prettyUrls":{"320":"sharma-2024-ni"},"prettyUrlList":["sharma-2024-ni"],"summary":"Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage ‘nutritional immunity’ to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into ‘oncobiotics’ for a multi-layered approach to cancer therapy.","prettyUrl":"sharma-2024-ni","following":false,"created":"02/28/2024","featured":false,"publishedDate":"02/28/2024","urlOrId":"sharma-2024-ni","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"93d86797-404f-499e-9c5e-cbcf594d7e9a","title":"Dynamic establishment of recipient resident memory T cell repertoire after human intestinal transplantation","investigator":"Sykes, M","investigatorInstitution":"Columbia University Medical Center","publicationName":"eBioMedicine","researchArea":"Organ transplant","prettyUrls":{"319":"jiao-2024-ebm"},"prettyUrlList":["jiao-2024-ebm"],"summary":"Understanding formation of the human tissue resident memory T cell (TRM) repertoire requires longitudinal access to human non-lymphoid tissues. By applying flow cytometry and next generation sequencing to serial blood, lymphoid tissue, and gut samples from 16 intestinal transplantation (ITx) patients, we assessed the origin, distribution, and specificity of human TRMs at phenotypic and clonal levels. Donor age ≥1 year and blood T cell macrochimerism (peak level ≥4%) were associated with delayed establishment of stable recipient TRM repertoires in the transplanted ileum. T cell receptor (TCR) overlap between paired gut and blood repertoires from ITx patients was significantly greater than that in healthy controls, demonstrating increased gut-blood crosstalk after ITx. Crosstalk with the circulating pool remained high for years of follow-up. TCR sequences identifiable in pre-Tx recipient gut but not those in lymphoid tissues alone were more likely to populate post-Tx ileal allografts. Clones detected in both pre-Tx gut and lymphoid tissue had distinct transcriptional profiles from those identifiable in only one tissue. Recipient T cells were distributed widely throughout the gut, including allograft and native colon, which had substantial repertoire overlap. Both alloreactive and microbe-reactive recipient T cells persisted in transplanted ileum, contributing to the TRM repertoire. Our studies reveal human intestinal TRM repertoire establishment from the circulation, preferentially involving lymphoid tissue counterparts of recipient intestinal T cell clones, including TRMs. We have described the temporal and spatial dynamics affecting this active crosstalk between the circulating pool and the intestinal TRM pool.","prettyUrl":"jiao-2024-ebm","following":false,"created":"02/23/2024","featured":false,"publishedDate":"02/23/2024","urlOrId":"jiao-2024-ebm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a4d73c02-a9eb-4723-9ec0-4714960e2b03","title":"Humans with inherited pre-TCR-⍺ deficiency and ⍺β T cells","investigator":"Béziat, Vivien","investigatorInstitution":"Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children","publicationName":"Science","researchArea":"Immunocompetence","prettyUrls":{"318":"materna-2024-s"},"prettyUrlList":["materna-2024-s"],"summary":"We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-TCRa expression. Low circulating naïve αβ T cell counts at birth persisted over time, with normal memory αβ and high γδ T cell counts. Their TCRα repertoire was biased, suggesting that noncanonical thymic differentiation pathways can rescue αβ T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naïve αβ T cell counts but high γδ T cell counts. Although residual pre-TCRa expression drove the differentiation of more αβ T cells, autoimmune conditions were more frequent in these patients than in the general population.","prettyUrl":"materna-2024-s","following":false,"created":"01/16/2024","featured":false,"publishedDate":"02/21/2024","urlOrId":"materna-2024-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"50048097-6c99-48cc-a7cf-538c3428ae9b","title":"Cancer-specific CD8 T cell frequency at baseline in blood correlates with response to PD-1 blockade in Merkel cell carcinoma","investigator":"Pulliam, Thomas","investigatorInstitution":"University of Washington","publicationName":"","researchArea":"Cancer Immunotherapy","prettyUrls":{"317":"pulliam-2024-crm"},"prettyUrlList":["pulliam-2024-crm"],"summary":"Understanding immunotherapy response and resistance is challenging due to difficulty identifying cancer-specific CD8 T cells. Merkel cell carcinoma (MCC) is typically driven by Merkel cell polyomavirus (MCPyV), facilitating identification of cancer-specific T cells across patients. We characterized cancer-specific T cells in 35 MCC patients, including from a neoadjuvant anti-PD-1 trial. Higher MCPyV-specific CD8 T-cell frequency in pre-treatment blood (but not tumors) correlated with response (p=0.0056). Single cell RNAseq revealed MCPyV-specific CD8 T cells in blood with increased stem/memory signatures and decreased exhaustion signatures relative to their intratumoral counterparts. The number of circulating cancer-specific T cells appears most linked to initial response to immunotherapy. Indeed, a longitudinal study showed loss of MHC-I on tumor cells during newly acquired resistance despite abundant cancer-specific CD8 T cells in blood. (original) These results suggest that blood acts as an important reservoir of cancer-specific CD8 T cells and suggests adoptive cell therapies may be particularly effective in patients without such cells.","prettyUrl":"pulliam-2024-crm","following":false,"created":"03/10/2023","featured":false,"publishedDate":"02/08/2024","urlOrId":"pulliam-2024-crm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"14e895c9-fdf5-4704-9945-c11ac03f737f","title":"The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda","investigator":"Edus H. Warren","investigatorInstitution":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center","publicationName":"","researchArea":"Cancer","prettyUrls":{"316":"ravishankar-2024-jem"},"prettyUrlList":["ravishankar-2024-jem"],"summary":"Coming Soon...","prettyUrl":"ravishankar-2024-jem","following":false,"created":"11/08/2023","featured":false,"publishedDate":"01/29/2024","urlOrId":"ravishankar-2024-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"89794211-d4aa-45b5-a5f2-0ef205509a79","title":"Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy","investigator":"Mansfield, Aaron","investigatorInstitution":"Division of Medical Oncology, Mayo Clinic","publicationName":"Journal for ImmunoTherapy of Cancer","researchArea":"Cancer Immunotherapy","prettyUrls":{"315":"desai-2023-jitc"},"prettyUrlList":["desai-2023-jitc"],"summary":"Background: Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.\n\nMethods: We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral\nblood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. Results We identified 4.2 million and 12 thousand\ncomplementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with\n2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a\nhigh number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases.\n\nConclusions: We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.","prettyUrl":"desai-2023-jitc","following":false,"created":"06/06/2023","featured":false,"publishedDate":"01/04/2024","urlOrId":"desai-2023-jitc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b9107078-7d40-44ff-9ae6-1f26c65dff73","title":"Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals","investigator":"Notarangelo, Luigi","investigatorInstitution":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health","publicationName":"Journal of Allergy and Clinical Immunology","researchArea":"Infectious Disease","prettyUrls":{"314":"delmonte-2023-jaci"},"prettyUrlList":["delmonte-2023-jaci"],"summary":"Background: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome.\n\nObjectives: We studied the breadth and magnitude of the T-cell responses in COVID-19 patients and in individuals with inborn errors of immunity (IEI) who had received COVID-19 mRNA vaccine.\n\nMethods: Utilizing high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor β (TRB) repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and in healthy controls, we quantified HLA class-I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in COVID-19 patients, including a sub-cohort of anti-type I interferon (IFN-I)-positive patients.\n\nResults: Our analysis revealed that elderly COVID-19 patients with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class-II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEI, including those who had failed to seroconvert.\n\nConclusions: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-I antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEI.","prettyUrl":"delmonte-2023-jaci","following":false,"created":"04/19/2023","featured":false,"publishedDate":"01/04/2024","urlOrId":"delmonte-2023-jaci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b07139f8-baa4-48ae-abd4-1ed751396b80","title":"Unstable regulatory and autoreactive effector T cells in patients with FOXP3 mutations","investigator":"Borna, Šimon","investigatorInstitution":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine","publicationName":"Science Translational Medicine","researchArea":"Basic Immunology","prettyUrls":{"313":"borna-2023-fi"},"prettyUrlList":["borna-2023-fi"],"summary":"Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX to those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multi-omic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers including CD25 and FOXP3.  Functional experiments with CRISPR/Cas9-mediated FOXP3 knock-out Tregs and Tregs from patients with IPEX indicated that the patients’ Tregs gain a Th2 skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation, indicated that Tregs expressing non-mutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.","prettyUrl":"borna-2023-fi","following":false,"created":"11/06/2023","featured":false,"publishedDate":"12/20/2023","urlOrId":"borna-2023-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2c853ddc-1f30-4134-8c7d-cdd9db5a3a61","title":"Autoreactive T cells target peripheral nerves in Guillain–Barré syndrome","investigator":"Latorre, Daniela","investigatorInstitution":"ETH Zurich, Institute of Microbiology, Human Neuroimmunology Group","publicationName":"Nature","researchArea":"Autoimmune Disorders","prettyUrls":{"311":"sukenikova-2023-n"},"prettyUrlList":["sukenikova-2023-n"],"summary":"Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.","prettyUrl":"sukenikova-2023-n","following":false,"created":"10/19/2023","featured":false,"publishedDate":"12/19/2023","urlOrId":"sukenikova-2023-n","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f4d7fe41-ce2d-4865-96b4-41e44fd2f87e","title":"TCR sequencing of HBRV stimulated cells, Crohn's blood, lymph node and colon, and blood and lymph node in primary biliary cholangitis","investigator":"Mason, Andrew","investigatorInstitution":"University of Alberta, Department of Medicine","publicationName":"","researchArea":"Basic Immunology","prettyUrls":{"310":"mason-2023"},"prettyUrlList":["mason-2023"],"summary":"HBRV stilumated cells: Intrahepatic lymphocytes obtained by flushing the liver of Primary Biliary Cholangitis patients undergoing transplant were stimulated with Env (E) and Gag (G) peptides from the Human Betaretrovirus (HBRV) and activated CD8+ CD137+ and CD4+ CD154+ were sorted and sequenced.\n\nCrohn’s: Samples obtained from pediatric and adult Crohn's disease patients were sequenced for their TCR. TP-C identifies Colon Tissue samples from pediatric patients, TP-LN identifies Lymph Node samples from pediatric patients, GR identifies whole blood samples from adult Crohn's disease patients and CD-LN identifies lymph node samples obtained from adult Crohn's disease patients.\n\nPrimary Biliary Cholangitis: TCR sequences obtained from Intrahepatic Lymphocyte (IHL) whole blood, Lymph nodes (LN), Whole Blood (RV) and Sorted CD4+ and CD8+ cells from whole blood (RV-CD4 or CD8). Serial RV samples with years indicating year of collection are also indicated in the sample ID.","prettyUrl":"mason-2023","following":false,"created":"11/28/2023","featured":false,"publishedDate":"12/06/2023","urlOrId":"mason-2023","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"11a66867-470a-4672-a63f-a30d0a59ece0","title":"Plasticity of intragraft alloreactive T cell clones in human gut correlates with transplant outcomes","investigator":"Sykes, Megan","investigatorInstitution":"Columbia Center for Translational Immunology, Department of Medicine, Columbia University","publicationName":"Journal of Experimental Medicine","researchArea":"Organ transplant","prettyUrls":{"309":"fu-2023-jem"},"prettyUrlList":["fu-2023-jem"],"summary":"The site of transition between tissue resident memory (TRM) and circulating phenotypes of T cells is unknown. We integrated clonotype, alloreactivity and gene expression profiles of graft-repopulating recipient T cells in the intestinal mucosa at the single cell level after human intestinal transplantation. Host-versus-graft (HvG)-reactive T cells mainly distributed to TRM, Teff/TRM and T follicular helper compartments. RNA velocity analysis demonstrated a trajectory from TRM to effector T (Teff)/TRM clusters in association with rejection. By integrating pre- and post-Tx mixed lymphocyte reaction-determined alloreactive repertoires, we observed that pre-existing HvG-reactive T cells that demonstrated tolerance in the circulation were dominated by TRM profiles in quiescent allografts. Putative de novo HvG-reactive clones showed a transcriptional profile skewed to cytotoxic effectors in rejecting grafts. Inferred protein regulon network analysis revealed upstream regulators that accounted for the effector and tolerant T cell states. We demonstrate Teff/TRM interchangeability for individual T cell clones with known (allo)recognition in human gut, providing novel insight into TRM biology.","prettyUrl":"fu-2023-jem","following":false,"created":"02/13/2023","featured":false,"publishedDate":"11/20/2023","urlOrId":"fu-2023-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"55029ec5-db82-48b2-b1d6-3e2acbc4c96f","title":"Tumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient","investigator":"Lien, Scott","investigatorInstitution":"Department of Immunology, University of Toronto, Toronto","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"308":"lien-2023-nc"},"prettyUrlList":["lien-2023-nc"],"summary":"Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While the majority of research on T cell exhaustion and PD-1 blockade has been focused on conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy. We find clonally expanded γδ T cells in the blood and tumor after pembrolizumab treatment, and this Vγ2Vδ1 clonotype recognizes Merkel cancer cells in a TCR-dependent manner. Notably, the intra-tumoral γδ T cells in the MCC patient are characterized by higher expression of PD-1 and TIGIT, relative to conventional CD4 and CD8 T cells. Our results demonstrate that innate-like T cells could also contribute to an anti-tumor response after PD-1 blockade.","prettyUrl":"lien-2023-nc","following":false,"created":"11/06/2023","featured":false,"publishedDate":"11/14/2023","urlOrId":"lien-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"71696fdf-c819-4a8f-b7c2-57646c03b25d","title":"Comprehensive immune profiling of SARS-CoV-2 infected kidney transplant patients","investigator":"Fenninger, Franz","investigatorInstitution":"Department of Medicine, University of British Columbia","publicationName":"","researchArea":"Organ transplant","prettyUrls":{"307":"fenninger-2023-ft"},"prettyUrlList":["fenninger-2023-ft"],"summary":"The immune responses of kidney transplant recipients against SARS-CoV-2 remains under studied. In this prospective pilot study, we performed comprehensive immune profiling using cellular, proteomic, and serologic assays on a cohort of 9 kidney transplant recipients and 12 non-transplant individuals diagnosed with COVID-19. Our data show that in addition to having reduced SARS-CoV-2 specific antibody levels, kidney transplant recipients exhibited significant cellular differences including a decrease in naïve - but increase in effector T cells, a high number of CD28+ CD4 effector memory T cells, and increased CD8 T memory stem cells compared with non-transplant patients. Furthermore, transplant patients had lower concentrations of serum cytokine MIP-1β as well as a less diverse T cell receptor repertoire. Overall, our results show that compared to non-transplant patients, kidney transplant recipients with SARS-CoV-2 infection exhibit an immunophenotype that is reminiscent of the immune signature observed in patients with severe COVID-19.","prettyUrl":"fenninger-2023-ft","following":false,"created":"10/18/2023","featured":false,"publishedDate":"10/19/2023","urlOrId":"fenninger-2023-ft","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"44a0d585-1966-47db-9e32-8919277d07bf","title":"Neoepitope-specific vaccination of patients with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles","investigator":"Boschert, Tamara","investigatorInstitution":"CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ) /Faculty of Biosciences, Heidelberg University/Helmholtz Institute for Translational Oncology (HI-TRON) & BioMed X GmbH","publicationName":"BioRxiv","researchArea":"Cancer Immunotherapy","prettyUrls":{"306":"boschert-2023-nm"},"prettyUrlList":["boschert-2023-nm"],"summary":"Coming Soon...","prettyUrl":"boschert-2023-nm","following":false,"created":"04/05/2023","featured":false,"publishedDate":"10/13/2023","urlOrId":"boschert-2023-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"743cd8c2-6d03-4448-a46e-13fae4487ebd","title":"Fc-enhanced anti-CTLA-4 antibody effects on T cell compartment","investigator":"Chloe Delepine","investigatorInstitution":"Agenus, Inc.","publicationName":"","researchArea":"Cancer Immunotherapy","prettyUrls":{"305":"delepine-2023-nm"},"prettyUrlList":["delepine-2023-nm"],"summary":"Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.","prettyUrl":"delepine-2023-nm","following":false,"created":"09/20/2023","featured":false,"publishedDate":"09/20/2023","urlOrId":"delepine-2023-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8f43f5d4-6f02-4121-960a-10bb5f8d67b0","title":"Tumor-resident Lactobacillus iners confers chemoradiation resistance through lactate-induced metabolic rewiring","investigator":"Colbert, Lauren E.","investigatorInstitution":"The University of Texas M.D. Anderson Cancer Center","publicationName":"Cancer Cell","researchArea":"Cancer","prettyUrls":{"303":"colbert-2023-cc"},"prettyUrlList":["colbert-2023-cc"],"summary":"Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in cervical cancer patients through a combined approach of deep microbiome sequencing, sequential, targeted bacterial culture and in vitro assays. We identify that an obligate L-lactate producing lactic acid bacteria found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring of tumors. Genomically similar L-lactate producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal cancer, lung cancer, head and neck cancer and skin cancer. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways to cause therapy resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.","prettyUrl":"colbert-2023-cc","following":false,"created":"09/05/2023","featured":false,"publishedDate":"09/07/2023","urlOrId":"colbert-2023-cc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"49a31e80-cc36-41f9-a915-d95835c3324e","title":"NL-201 Upregulates MHC-I Expression and Intratumoral T-cell Receptor Diversity, and Demonstrates Robust Antitumor Activity as Monotherapy and in Combination with PD-1 Blockade","investigator":"Huard, Justin","investigatorInstitution":"Neoleukin Therapuetics","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"302":"cm-2023-cir"},"prettyUrlList":["cm-2023-cir"],"summary":"Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, IL2 receptor alpha (IL2Rα)-independent agonist of the receptors for IL2 and IL15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICI). Here, we report that NL-201 monotherapy converts 'cold' tumor microenvironments (TME) to immunologically 'hot' states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. In addition, the combination of NL-201 and anti-PD-1 resulted in complementary antitumor activity in the immunologically 'cold' and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti-PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the TME. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.","prettyUrl":"cm-2023-cir","following":false,"created":"06/30/2023","featured":false,"publishedDate":"08/28/2023","urlOrId":"cm-2023-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a7bf2c51-6fca-420b-a275-17a05831b725","title":"CDK4/6 inhibition sensitizes intracranial tumors to PD-1 blockade in preclinical models of brain metastasis","investigator":"Brastianos, Priscilla","investigatorInstitution":"Massachusetts General Hospital","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"301":"nayyar-2023-ccr"},"prettyUrlList":["nayyar-2023-ccr"],"summary":"Purpose: Brain metastases are associated with high morbidity and often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to PD-1 inhibition in mouse models of melanoma and breast cancer brain metastasis.\n\nExperimental Design: Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor immune microenvironments was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry and T cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T cell development.\n\nResults: We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The tumor immune microenvironment, which differed based on anatomical location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T cell subsets, depleted CD4+ regulatory T (TREG) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted TREG cells.\n\nConclusions: Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases.","prettyUrl":"nayyar-2023-ccr","following":false,"created":"08/03/2023","featured":false,"publishedDate":"08/07/2023","urlOrId":"nayyar-2023-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a2e2a003-d454-48b0-b024-bd31bd655c72","title":"Low immune infiltrate level is associated with worse overall survival and complete loss of TP53 and RB1 in pleomorphic rhabdomyosarcoma","investigator":"Futreal, P Anderw","investigatorInstitution":"Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center,","publicationName":"Human Genetics and Genomics Advances","researchArea":"Cancer","prettyUrls":{"300":"beird-2023-hgga"},"prettyUrlList":["beird-2023-hgga"],"summary":"Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low  levels in other rhabdomyosarcoma subtypes. Higher immune infiltrate levels were associated with improved overall survival while lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration.","prettyUrl":"beird-2023-hgga","following":false,"created":"07/28/2023","featured":false,"publishedDate":"08/02/2023","urlOrId":"beird-2023-hgga","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"42f65f69-9967-468b-b6dd-82971f9c9d92","title":"Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors","investigator":"Rudqvist, Nils-Petter","investigatorInstitution":"Weill Cornell Medicine","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"299":"rudqvist-2023-nc"},"prettyUrlList":["rudqvist-2023-nc"],"summary":"Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments.","prettyUrl":"rudqvist-2023-nc","following":false,"created":"07/31/2023","featured":false,"publishedDate":"08/02/2023","urlOrId":"rudqvist-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fa503086-4201-46bb-adcf-be765e1830eb","title":"Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma","investigator":"Mustjoki, Satu","investigatorInstitution":"Hematology Research Unit, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center","publicationName":"Cancer Research Communications","researchArea":"Cancer","prettyUrls":{"298":"lee-2023-crc"},"prettyUrlList":["lee-2023-crc"],"summary":"The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well understood. In this study, we analyzed the tumor samples (n = 58) from treatment-naïve patients with renal cell carcinoma (RCC), \"pre-rapidly expanded\" TILs (pre-REP TIL, n = 15) and \"rapidly expanded\" TILs (REP TIL, n = 25) according to a clinical-grade TIL production protocol, with single-cell RNA (scRNA)+TCRαβ-seq (TCRαβ sequencing), TCRβ-sequencing (TCRβ-seq), and flow cytometry. REP TILs encompassed a greater abundance of CD4+ than CD8+ T cells, with increased LAG-3 and low PD-1 expressions in both CD4+ and CD8+ T cell compartments compared with the pre-REP TIL and tumor T cells. The REP protocol preferentially expanded small clones of the CD4+ phenotype (CD4, IL7R, KLRB1) in the TME, indicating that the largest exhausted T cell clones in the tumor do not expand during the expansion protocol. In addition, by generating a catalog of RCC-associated TCR motifs from >1,000 scRNA+TCRαβ-seq and TCRβ-seq RCC, healthy and other cancer sample cohorts, we quantified the RCC-associated TCRs from the expansion protocol. Unlike the low-remaining amount of anti-viral TCRs throughout the expansion, the quantity of the RCC-associated TCRs was high in the tumors and pre-REP TILs but decreased in the REP TILs. Our results provide an in-depth understanding of the origin, phenotype, and TCR specificity of RCC TIL products, paving the way for a more rationalized production of TILs.","prettyUrl":"lee-2023-crc","following":false,"created":"03/27/2023","featured":false,"publishedDate":"07/24/2023","urlOrId":"lee-2023-crc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ee5df40f-f728-4731-bb7c-d52f8aaa3505","title":"Hedgehog Costimulation During Ischemia Reperfusion Injury Potentiates Cytokine and Homing Responses of CD4+ T Cells","investigator":"Jane-wit, Dan","investigatorInstitution":"Yale University","publicationName":"Frontiers in Immunology","researchArea":"Other","prettyUrls":{"297":"wang-2023-fi"},"prettyUrlList":["wang-2023-fi"],"summary":"Introduction: Ischemia reperfusion injury (IRI) confers worsened outcomes and is an increasing clinical problem in solid organ transplantation. Previously, we identified a \"PtchHi\" T-cell subset that selectively received costimulatory signals from endothelial cell-derived Hedgehog (Hh) morphogens to mediate IRI-induced vascular inflammation.\n\nMethods: Here, we used multi-omics approaches and developed a humanized mouse model to resolve functional and migratory heterogeneity within the PtchHi population.\n\nResults: Hh-mediated costimulation induced oligoclonal and polyclonal expansion of clones within the PtchHi population, and we visualized three distinct subsets within inflamed, IRI-treated human skin xenografts exhibiting polyfunctional cytokine responses. One of these PtchHi subsets displayed features resembling recently described T peripheral helper cells, including elaboration of IFN-y and IL-21, expression of ICOS and PD-1, and upregulation of positioning molecules conferring recruitment and retention within peripheral but not lymphoid tissues. PtchHi T cells selectively homed to IRI-treated human skin xenografts to cause accelerated allograft loss, and Hh signaling was sufficient for this process to occur.\n\nDiscussion: Our studies define functional heterogeneity among a PtchHi T-cell population implicated in IRI.","prettyUrl":"wang-2023-fi","following":false,"created":"07/17/2023","featured":false,"publishedDate":"07/17/2023","urlOrId":"wang-2023-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c6516d68-8691-4864-a9b7-56cc178623cc","title":"Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma","investigator":"Coffey, David G.","investigatorInstitution":"Sylvester Comprehensive Cancer Center, University of Miami","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"296":"coffey-2023-nc"},"prettyUrlList":["coffey-2023-nc"],"summary":"The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. We comprehensively profiled the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of uncovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterized the immune landscape in 23 patients before and one year after lenalidomide exposure. We compared patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observed that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.","prettyUrl":"coffey-2023-nc","following":false,"created":"12/06/2022","featured":false,"publishedDate":"06/30/2023","urlOrId":"coffey-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fb2f87ff-6d7b-4b4a-afee-3c78b185e610","title":"Phototherapy restores deficient type I interferon production and enhances antitumor responses in mycosis fungoides","investigator":"Clark, Rachael","investigatorInstitution":"Brigham and Women's Hospital","publicationName":"Journal of Investigative Dermatology","researchArea":"Cancer","prettyUrls":{"295":"clark-2023-jid"},"prettyUrlList":["clark-2023-jid"],"summary":"Transcriptional profiling demonstrated markedly reduced type I IFN gene expression in untreated mycosis fungoides (MF) skin lesions compared with that in healthy skin. Type I IFN expression in MF correlated with antigen-presenting cell-associated IRF5 before psoralen plus UVA therapy and epithelial ULBP2 after therapy, suggesting an enhancement of epithelial type I IFN. Immunostains confirmed reduced baseline type I IFN production in MF and increased levels after psoralen plus UVA treatment in responding patients. Effective tumor clearance was associated with increased type I IFN expression, enhanced recruitment of CD8+ T cells into skin lesions, and expression of genes associated with antigen-specific T-cell activation. IFNk, a keratinocyte-derived inducer of type I IFNs, was increased by psoralen plus UVA therapy and expression correlated with upregulation of other type I IFNs. In vitro, deletion of keratinocyte IFNk decreased baseline and UVA-induced expression of type I IFN and IFN response genes. In summary, we find a baseline deficit in type I IFN production in MF that is restored by psoralen plus UVA therapy and correlates with enhanced antitumor responses. This may explain why MF generally develops in sun-protected skin and suggests that drugs that increase epithelial type I IFNs, including topical MEK and EGFR inhibitors, may be effective therapies for MF.","prettyUrl":"clark-2023-jid","following":false,"created":"06/15/2023","featured":false,"publishedDate":"06/22/2023","urlOrId":"clark-2023-jid","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"24e260ad-9956-4062-a9a1-7b28b803dc54","title":"The overlap of blood and skin T-cell clones in early-stage mycosis fungoides","investigator":"Nikbakht, Neda","investigatorInstitution":"Thomas Jefferson University, Department of Dermatology and Cutaneous Biology","publicationName":"Blood Advances","researchArea":"Cancer","prettyUrls":{"294":"joffe-2023-ba"},"prettyUrlList":["joffe-2023-ba"],"summary":"Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma that initially starts in the skin but can progress to involve blood with significant mortality in late stages. The presence of a dominant T-cell clone in the blood of early-stage MF appears to be associated with a poor prognosis. However, the identity of dominant blood T-cell clones and the degree of overlap between T-cell repertoires of blood and skin in MF have not been fully interrogated. Here, we evaluated the relationship of blood and skin T-cell repertoires and their relevance to prognosis in MF. We used high-throughput sequencing to interrogate the T-cell receptor (TCR) complementarity determining region 3 sequences in blood and skin of MF patients at the Jefferson Cutaneous Lymphoma Clinic (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell repertoire overlap metric (Morisita’s index) and diversity measure (Simpson’s clonality score). Time to systemic treatment (TTST) was calculated as the time from initial diagnosis to initiation of first systemic therapy. \n60 MF patients with no blood involvement were enrolled. 28% had a dominant clone in blood; of these, 18% were identical to dominant skin clones and 82% were distinct from the dominant clones identified in skin. We found that MF patients with discordant dominant TCR clones in blood and skin had a longer TTST when compared to the identical cohort (P=0.0057). Furthermore, patients with discordant dominant clones had a lower degree of T-cell repertoire overlap between blood and skin (P<0.0001) and higher blood T-cell repertoire diversity scores (P=0.013) when compared to the identical group. Our data shows that MF patients with dominant clones in blood segregate into two cohorts with distinct prognoses based on the identity of their peripheral T-cell clones.","prettyUrl":"joffe-2023-ba","following":false,"created":"06/07/2023","featured":false,"publishedDate":"06/20/2023","urlOrId":"joffe-2023-ba","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d6a06643-4f97-4de7-aa3d-d1f3f0d0b6d1","title":"Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results","investigator":"Hassan, Raffit","investigatorInstitution":"Thoracic and GI Malignancies Branch, NCI","publicationName":"Nature Medicine","researchArea":"Cancer","prettyUrls":{"293":"hassan-2023-nm"},"prettyUrlList":["hassan-2023-nm"],"summary":"The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 .","prettyUrl":"hassan-2023-nm","following":false,"created":"06/01/2023","featured":false,"publishedDate":"06/01/2023","urlOrId":"hassan-2023-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b8360822-76fc-47a3-b453-6f7ed056c0f5","title":"Differentiation of exhausted CD8 T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory","investigator":"Lauer, Georg M.","investigatorInstitution":"Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School","publicationName":"Nature Immunology","researchArea":"Other","prettyUrls":{"292":"tonnerre-2021-ni"},"prettyUrlList":["tonnerre-2021-ni"],"summary":"T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Analysis of antigen-specific CD8+ T cells before and after antigen removal in human hepatitis c virus (HCV) infection confirmed pervasive phenotypic, functional, and transcriptional differences between exhausted and memory CD8+ T cells. After viral cure, we observed broad phenotypic and transcriptional changes in clonally stable exhausted T-cell populations suggesting differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for shorter periods of time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved acute HCV infection. Thus, duration of T cell stimulation impacts the ability to recover from exhaustion, as antigen removal after long-term T cell exhaustion is insufficient for the development of key T cell memory characteristics.","prettyUrl":"tonnerre-2021-ni","following":false,"created":"06/04/2021","featured":false,"publishedDate":"05/24/2023","urlOrId":"tonnerre-2021-ni","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e69bc69b-98b5-4585-a220-afd95f731170","title":"Perturbations of the T-cell immune repertoire in kidney transplant rejection","investigator":"Sarwal, Minnie M","investigatorInstitution":"Department of Surgery, Division of Multi Organ Transplantation, University of California, San Francisco","publicationName":"Frontiers in Immunology","researchArea":"Organ transplant","prettyUrls":{"290":"sigdel-2022-fi"},"prettyUrlList":["sigdel-2022-fi"],"summary":"In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.","prettyUrl":"sigdel-2022-fi","following":false,"created":"04/24/2023","featured":false,"publishedDate":"05/23/2023","urlOrId":"sigdel-2022-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e05475e7-2695-4b91-b89e-64de88cdc6ab","title":"Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling","investigator":"Rosenzweig, Sergio D.","investigatorInstitution":"Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health","publicationName":"Nature Communications","researchArea":"Immunocompetence","prettyUrls":{"291":"nunes-santos-2023-nc"},"prettyUrlList":["nunes-santos-2023-nc"],"summary":"We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)-6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets.","prettyUrl":"nunes-santos-2023-nc","following":false,"created":"11/10/2022","featured":false,"publishedDate":"05/22/2023","urlOrId":"nunes-santos-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b11ccf4a-cca7-452b-8345-b0b23c565855","title":"The prospect of universal coronavirus immunity: characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses","investigator":"Soni, Mithil","investigatorInstitution":"Columbia Center for Translational Immunology, Department of Medicine, Columbia University","publicationName":"Frontiers in Immunology","researchArea":"Infectious Disease","prettyUrls":{"289":"mithil-2023-fi"},"prettyUrlList":["mithil-2023-fi"],"summary":"T cell immunity plays a central role in clinical outcomes of Coronavirus Infectious Disease 2019 (COVID-19). Therefore, T cell-focused vaccination or cellular immunotherapy might provide enhanced protection for immunocompromised patients. Pre-existing T cell memory recognizing SARS-CoV2 antigens antedating COVID-19 infection or vaccination, may have developed as an imprint of prior infections with endemic non-SARS human coronaviruses (hCoVs) OC43, HKU1, 229E, NL63, pathogens of “common cold”. In turn, SARS-CoV2-primed T cells may recognize emerging variants or other hCoV viruses and modulate the course of subsequent hCoV infections. Cross-immunity between hCoVs and SARS-CoV2 has not been well characterized. Here, we systematically investigated T cell responses against the immunodominant SARS-CoV2 spike, nucleocapsid and membrane proteins and corresponding antigens from α- and β-hCoVs among vaccinated, convalescent, and unexposed subjects. Broad T cell immunity against all tested SARS-CoV2 antigens emerged in COVID-19 survivors. In convalescent and in vaccinated individuals, SARS-CoV2 spike-specific T cells reliably recognized most SARS-CoV2 variants, however cross-reactivity against the omicron variant was reduced by approximately 50%. Responses against spike, nucleocapsid and membrane antigens from endemic hCoVs were more extensive in COVID-19 survivors than in unexposed subjects and displayed cross-reactivity between α- and β-hCoVs. In some, non-SARS hCoV-specific T cells demonstrated a prominent non-reciprocal cross-reactivity with SARS-CoV2 antigens, whereas a distinct anti-SARS-CoV2 immunological repertoire emerged post-COVID-19, with relatively limited cross-recognition of non-SARS hCoVs. Based on this cross-reactivity pattern, we established a strategy for in-vitro expansion of universal anti-hCoV T cells for adoptive immunotherapy. Overall, these results have implications for the future design of universal vaccines and cell-based immune therapies against SARS- and non-SARS-CoVs.","prettyUrl":"mithil-2023-fi","following":false,"created":"04/21/2023","featured":false,"publishedDate":"04/21/2023","urlOrId":"mithil-2023-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8129cdf8-cd65-4136-8a4c-32f145f10a27","title":"Reduced skin T-cell receptor diversity in large cell transformed mycosis fungoides","investigator":"Nikbakht, Neda","investigatorInstitution":"Department of Dermatology and Cutaneous Biology, Thomas Jefferson University","publicationName":"Journal of Investigative Dermatology","researchArea":"Dermatology","prettyUrls":{"288":"gleason-2023-jid"},"prettyUrlList":["gleason-2023-jid"],"summary":"We assess changes in the T-cell repertoire diversity in an aggressive subtype of cutaneous T-cell lymphoma. Mycosis fungoides (MF) is a type of T-cell lymphoma that originates in the skin and can progress to extracutaneous sites in late stages. Large cell transformed mycosis fungoides (LCT-MF) is an aggressive subtype of MF associated with a higher likelihood of malignancy progression and mortality. Given that T-cell repertoire diversity and skin tumor cell frequency (TCF) may influence prognosis, we sought to investigate these metrics in LCT-MF. We sequenced the complementarity determining regions of T-cell receptor genes in skin biopsies and blood samples of aged-matched healthy subjects, non-leukemic MF and LCT-MF. Overall, our results demonstrate that while lesional skin of LCT-MF differs from MF in clonal diversity in both late and early-stage, its malignant T-cell frequency differs only in early-stage. Our data can provide insight into the tissue specific origin of early T-cell transformation events in MF.","prettyUrl":"gleason-2023-jid","following":false,"created":"04/10/2023","featured":false,"publishedDate":"04/19/2023","urlOrId":"gleason-2023-jid","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f1e157b6-527f-47a5-aae9-6b48aa7978b5","title":"Neoadjuvant enoblituzumab in localized prostate cancer: a single arm, phase 2 trial","investigator":"Shenderov, Eugene","investigatorInstitution":"Department of Oncology, Johns Hopkins School of Medicine","publicationName":"Nature Medicine","researchArea":"Cancer","prettyUrls":{"287":"shenderov-2023-nm"},"prettyUrlList":["shenderov-2023-nm"],"summary":"B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA0) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA0 with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA0 rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.","prettyUrl":"shenderov-2023-nm","following":false,"created":"02/27/2023","featured":false,"publishedDate":"04/14/2023","urlOrId":"shenderov-2023-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"891e78f0-95af-4e62-8910-ade6c90520a2","title":"Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy","investigator":"Lee, John K","investigatorInstitution":"Fred Hutchinson Cancer Center and University of Washington","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"286":"bhatia-2023-nc"},"prettyUrlList":["bhatia-2023-nc"],"summary":"Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling cell surface antigen for therapeutic targeting in prostate cancer. We report broad expression of STEAP1 relative to prostate-specific membrane antigen (PSMA) in lethal metastatic prostate cancers and the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrate reactivity in low antigen density, antitumor activity across metastatic prostate cancer models, and safety in a human STEAP1 knock-in mouse model. STEAP1 antigen escape is a recurrent mechanism of treatment resistance and is associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein combined with STEAP1 CAR T cell therapy enhances antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading.","prettyUrl":"bhatia-2023-nc","following":false,"created":"03/30/2023","featured":false,"publishedDate":"03/30/2023","urlOrId":"bhatia-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ad7a2d37-a0bc-4d88-813e-6dd7d762a65b","title":"T cell receptor repertoire sequencing reveals chemotherapy-driven clonal expansion in colorectal liver metastases","investigator":"Flatmark, Kjersti","investigatorInstitution":"Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital","publicationName":"GigaScience","researchArea":"Cancer","prettyUrls":{"285":"hoye-2023-gs"},"prettyUrlList":["hoye-2023-gs"],"summary":"Background: Colorectal liver metastasis (CLM) is a leading cause of colorectal cancer mortality, and the response to immune checkpoint inhibition (ICI) in microsatellite stable CRC has been disappointing. Administration of cytotoxic chemotherapy may cause increased density of tumour infiltrating T cells, which has been associated with improved response to ICI. This study aimed to quantify and characterize T cell infiltration in CLM using T cell receptor (TCR) repertoire sequencing.\n\nMethods: Eighty-five resected CLM from patients included in the Oslo CoMet study were subjected to TCR repertoire sequencing. Thirty-five and 15 patients had received neoadjuvant chemotherapy (NACT) within a short or long interval, respectively, prior to resection, while 35 patients had not been exposed to NACT. T cell fractions were calculated, repertoire clonality was analysed based on Hill evenness curves, and TCR sequential convergence was assessed using network analysis.\n\nFindings: Increased T cell fractions (10·6% vs 6·3%) were detected in CLM exposed to NACT within a short interval prior to resection, while modestly increased clonality was observed in NACT exposed tumours independently of the timing of NACT administration and surgery. While private clones made up >90% of detected clones, network connectivity analysis revealed that public clones contributed the majority of TCR sequence convergence.\n\nInterpretation: TCR repertoire sequencing can be used to quantify T cell infiltration and clonality in clinical samples. This study provides evidence to support chemotherapy-driven T cell clonal expansion in CLM in a clinical context.","prettyUrl":"hoye-2023-gs","following":false,"created":"09/22/2022","featured":false,"publishedDate":"02/27/2023","urlOrId":"hoye-2023-gs","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"88f526f9-93e2-459a-aaab-e7572da91e74","title":"Microbial peptides activate tumor-infiltrating lymphocytes in glioblastoma","investigator":"Naghavian,Reza","investigatorInstitution":"Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich","publicationName":"Nature","researchArea":"Cancer Immunotherapy","prettyUrls":{"284":"naghavian-2023-n"},"prettyUrlList":["naghavian-2023-n"],"summary":"Microbial organisms play key roles in numerous physiological processes in the human body and have recently been shown to modify the response to cancer radiotherapy and immune checkpoint inhibitors. Here, we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumor cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumor-infiltrating lymphocytes (TILs) recognize tumor-derived bacterial peptides. Bacterial peptides eluted from HLA-II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4+ T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumor antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumor-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumor antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumor vaccination approaches.","prettyUrl":"naghavian-2023-n","following":false,"created":"02/14/2023","featured":false,"publishedDate":"02/27/2023","urlOrId":"naghavian-2023-n","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1405901d-9e88-4c21-9f4a-07f530b2aafa","title":"Clonally expanded HIV-1 proviruses with 5’-Leader defects can give rise to nonsuppressible residual viremia","investigator":"Simonetti, Francesco R.","investigatorInstitution":"Department of Medicine, Johns Hopkins University School of Medicine","publicationName":"Journal of Clinical Investigation","researchArea":"Infectious Disease","prettyUrls":{"283":"white-2023-jci"},"prettyUrlList":["white-2023-jci"],"summary":"Background: Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.\n\nMethods: We carried an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5'-Leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.\n\nResults: Clones carrying proviruses with 5'-Leader defects can cause persistent NSV up to ~103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor site (MSD) and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced non-infectious virions containing viral RNA but lacking Envelope.\n\nConclusion: These findings show that proviruses with 5'-Leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-Leader can help understanding failure to completely suppress viremia.","prettyUrl":"white-2023-jci","following":false,"created":"12/19/2022","featured":false,"publishedDate":"02/15/2023","urlOrId":"white-2023-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9a3204c8-3241-4dce-bb6a-7af4cc6be9ef","title":"Combination IFNβ and membrane-stable CD40L maximize tumor dendritic cell activation and lymph node trafficking to elicit systemic T-cell immunity","investigator":"Zheng, Hong","investigatorInstitution":"Moffitt Cancer Center and Research Institute","publicationName":"Cancer immunology research","researchArea":"Other","prettyUrls":{"282":"zheng-2023-cir"},"prettyUrlList":["zheng-2023-cir"],"summary":"Oncolytic viral therapies induce direct killing of tumor cells and activation of conventional dendritic cells (cDCs); however, cDC activation has not been optimized with current therapies. We evaluated adenoviral delivery of engineered membrane-stable CD40L (MEM40) and IFNβ to locally activate cDCs in mouse tumor models. Combined tumor MEM40 and IFNβ expression induced the highest cDC activation coupled with increased lymph node migration, increased systemic antitumor CD8+ T-cell responses, and regression of established tumors in a cDC1-dependent manner. MEM40+IFNβ combined with checkpoint inhibitors led to effective control of distant tumors and lung metastases. An oncolytic adenovirus (MEM-288) expressing MEM40+IFNβ in phase 1 clinical testing induced cancer cell loss concomitant with enhanced T-cell infiltration and increased systemic presence of tumor T-cell clonotypes in NSCLC patients. This approach to simultaneously target two major DC-activating pathways has potential to significantly impact the solid tumor immunotherapy landscape.","prettyUrl":"zheng-2023-cir","following":false,"created":"01/20/2023","featured":false,"publishedDate":"02/14/2023","urlOrId":"zheng-2023-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"218392a3-618b-4fbf-8785-3509684f8613","title":"A phase Ib trial evaluating the safety, efficacy, and immunologic effects of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer","investigator":"Page, David B.","investigatorInstitution":"Earle A. Chiles Research Institute, Providence Cancer Institute","publicationName":"NPJ Breast Cancer","researchArea":"Cancer","prettyUrls":{"281":"page-2023-npj"},"prettyUrlList":["page-2023-npj"],"summary":"Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200mg IV every 3 weeks) with either weekly paclitaxel (80mg/m2 weekly) or flat-dose capecitabine (2000mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n=4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n=6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted.","prettyUrl":"page-2023-npj","following":false,"created":"12/21/2022","featured":false,"publishedDate":"02/10/2023","urlOrId":"page-2023-npj","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2457f729-fa61-429c-a97b-6b0e1aed9130","title":"Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.","investigator":"Andrew Chow","investigatorInstitution":"Memorial Sloan Kettering Cancer Center","publicationName":"Cancer Cell","researchArea":"Cancer Immunotherapy","prettyUrls":{"280":"pai-2023-cc"},"prettyUrlList":["pai-2023-cc"],"summary":"Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed\nfor enhanced resolution of clonal T cell dynamics in cancer. Here, we report\nscRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor,\nadjacent normal tissues, and lymph nodes (LN), from patients who underwent\nresections for persistent or progressing lung cancers after immune checkpoint\nblockade (ICB). We found marked regional heterogeneity in CD8+ and CD4+ T cell\nphenotypes that was associated with heterogeneity in the presence of viable tumor\ncells. Regions with viable cancer cells were enriched for exhausted CD8+ T cells,\nregulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking\nindividual T cell clonotypes across tumor regions and tissues, combined with\nneoantigen specificity assays, revealed that TFH and tumor-specific exhausted CD8+\nT cells could be clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and\nprogressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to\nthe tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and\nCD4+ T cell clones revealed persistence in the peripheral blood for years after ICB\ntherapy; however, exhausted CD8+, Treg, and TFH cells had lower persistence relative\nto other subsets. Strikingly, the presence of clonally linked progenitors in the LN\nconferred greater longitudinal persistence. Altogether, this comprehensive\nscRNA/TCR-seq dataset with regional, clonal, and longitudinal resolution provides\nfundamental insights into the tissue distribution, differentiation trajectories, and\npersistence of the tumor-specific T cells that underlie clinical responses to ICB.","prettyUrl":"pai-2023-cc","following":false,"created":"02/05/2023","featured":false,"publishedDate":"02/09/2023","urlOrId":"pai-2023-cc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bed85d2c-c678-4ec7-b243-8e55588a7ca5","title":"Single-cell characterization of anti-LAG3+anti-PD1 treatment in melanoma patients","investigator":"Huuhtanen, Jani","investigatorInstitution":"Hematology Research Unit Helsinki, University of Helsinki","publicationName":"Journal of Clinical Investigation","researchArea":"Cancer","prettyUrls":{"279":"huuhtanen-2023-jci"},"prettyUrlList":["huuhtanen-2023-jci"],"summary":"Background: Relatlimab+nivolumab (anti-LAG3+anti-PD1) has been approved by FDA as a 1st-line therapy in stage III/IV melanoma, but its detailed effect on the immune system is unknown. \n\nMethods: We evaluated blood samples from 40 immunotherapy-naïve or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG3+anti-PD1 in a phase I trial (NCT01968109) using single-cell RNA and T cell receptor (TCR) sequencing (scRNA+TCRαβ-seq) combined with other multiomics profiling. \n\nResults: The highest LAG3 expression was noted in NK cells, regulatory T cells (Tregs), and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy resulting in an active phenotype. LAG3+ Tregs expanded but based on the transcriptome profile became metabolically silent during the treatment. Lastly, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained more cytotoxic and NK-like phenotype. \n\nConclusion: Anti-LAG3+anti-PD1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.","prettyUrl":"huuhtanen-2023-jci","following":false,"created":"02/07/2023","featured":false,"publishedDate":"02/08/2023","urlOrId":"huuhtanen-2023-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7f1ac13d-292c-43f6-a12e-4534a12900e1","title":"Impaired SARS-CoV-2 variant neutralization and CD8+ T cell responses following 3 doses of mRNA vaccines in myeloma: correlation with breakthrough infections","investigator":"Dhodapkar, Madhav V.","investigatorInstitution":"Department of Hematology/Medical Oncology, Emory University","publicationName":"Blood Cancer Discovery","researchArea":"Infectious Disease","prettyUrls":{"278":"azeem-2023-bcd"},"prettyUrlList":["azeem-2023-bcd"],"summary":"Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)–specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells.","prettyUrl":"azeem-2023-bcd","following":false,"created":"02/01/2023","featured":false,"publishedDate":"02/01/2023","urlOrId":"azeem-2023-bcd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a72d3b15-ce5a-483c-a15c-5f953a74680b","title":"Immunosequencing and profiling of T cells at the maternal-fetal interface in preterm labor and birth","investigator":"Gomez-Lopez, Nardhy","investigatorInstitution":"Department of Obstetrics and Gynecology, Wayne State University School of Medicine","publicationName":"Journal of Immunology","researchArea":"Immunocompetence","prettyUrls":{"277":"miller-2023-ji"},"prettyUrlList":["miller-2023-ji"],"summary":"T cells are implicated in the pathophysiology of preterm labor and birth, the leading cause of neonatal morbidity and mortality worldwide. Specifically, maternal decidual T cells infiltrate the chorioamniotic membranes in chronic chorioamnionitis (CCA), a placental lesion considered to reflect maternal anti-fetal rejection, leading to preterm labor and birth. However, the phenotype and TCR repertoire of decidual T cells in women with preterm labor and CCA have not been investigated. In this study, we used phenotyping, TCR sequencing, and functional assays to elucidate the molecular characteristics and Ag specificity of T cells infiltrating the chorioamniotic membranes in women with CCA who underwent term or preterm labor. Phenotyping indicated distinct enrichment of human decidual effector memory T cell subsets in cases of preterm labor with CCA without altered regulatory T cell proportions. TCR sequencing revealed that the T cell repertoire of CCA is characterized by increased TCR richness and decreased clonal expansion in women with preterm labor. We identified 15 clones associated with CCA and compared these against established TCR databases, reporting that infiltrating T cells may possess specificity for maternal and fetal Ags, but not common viral Ags. Functional assays demonstrated that choriodecidual T cells can respond to maternal and fetal Ags. Collectively, our findings provide, to our knowledge, novel insight into the complex processes underlying chronic placental inflammation and further support a role for effector T cells in the mechanisms of disease for preterm labor and birth. Moreover, this work further strengthens the contribution of adaptive immunity to the syndromic nature of preterm labor and birth.","prettyUrl":"miller-2023-ji","following":false,"created":"01/30/2023","featured":false,"publishedDate":"02/01/2023","urlOrId":"miller-2023-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a1b2d1a0-e3d1-4e6e-9669-e004ed04f4b8","title":"Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy","investigator":"Murakami, Naoka","investigatorInstitution":"Brigham and Women's Hospital, Division of Renal Medicine","publicationName":"Nature Communications","researchArea":"Organ transplant","prettyUrls":{"276":"dunlap-2023-nc"},"prettyUrlList":["dunlap-2023-nc"],"summary":"Kidney transplant recipients are at particular risk for developing tumors, many of which are now routinely treated with immune checkpoint inhibitors (ICIs); however, ICI therapy can precipitate transplant rejection. We utilized TCR sequencing to identify and track alloreactive T cells in a patient with melanoma who experienced kidney transplant rejection following ICI therapy. ICI therapy was associated with a sharp increase in circulating alloreactive CD8+ T cell clones, many of which were also detected in the rejected kidney but not at tumor sites. Longitudinal and cross-tissue TCR analyses revealed unintended expansion of alloreactive CD8+ T cells induced by ICI therapy for cancer, coinciding with ICI-associated organ rejection.","prettyUrl":"dunlap-2023-nc","following":false,"created":"10/29/2022","featured":false,"publishedDate":"01/30/2023","urlOrId":"dunlap-2023-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"885ef16f-5c7a-437a-a6cc-01872b6c8c58","title":"Host-specific differences in top-expanded TCR clonotypes correlate with divergent outcomes of anti-PD-L1 treatment in responders versus non-responders","investigator":"Wang, Jing H","investigatorInstitution":"Department of Medicine, University of Pittsburgh","publicationName":"Frontiers in Immunology","researchArea":"Cancer Immunotherapy","prettyUrls":{"275":"john-2023-fi"},"prettyUrlList":["john-2023-fi"],"summary":"Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, the responses to ICI treatment are highly variable in different individuals and the underlying mechanisms remain poorly understood.  Here, we employed a mouse squamous cell carcinoma (SCC) model where tumor-bearing recipients diverged into responders (R) versus non-responders (NR) upon anti-PD-L1 treatment. We performed in-depth TCR sequencing with immunoSEQ platform to delineate the differences in CD8 tumor-infiltrating lymphocytes (TILs).  We found that R and NR CD8 TILs both exhibited evidence of clonal expansion, suggesting activation regardless of response status.  We detected no differences in clonal expansion or clonal diversity indexes between R vs. NR.  However, the top expanded (>1%) TCR clonotypes appeared to be mutually exclusive between R and NR CD8 TILs, showing a preferential expansion of distinct TCR clonotypes in response to the same SCC tumor in R vs. NR.  Notably, the mutual exclusivity of TCR clonotypes in R vs. NR was only observed when top TCR clonotypes were counted, because such top-expanded clonotypes are present in the opposite outcome group at a much lower frequency.  Many TCR sequences were detected in only one recipient at a high frequency, implicating highly individualized anti-tumor immune responses.  We conclude that differences in the clonal frequency of top TCR clonotypes between R and NR CD8 TILs may be one of the factors underlying differential anti-PD-L1 responses. This notion may offer a novel explanation for variable ICI responses in different individuals, which may substantially impact the development of new strategies for personalized cancer immunotherapy.","prettyUrl":"john-2023-fi","following":false,"created":"01/30/2023","featured":false,"publishedDate":"01/30/2023","urlOrId":"john-2023-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"91a8f980-42f0-4385-b8eb-ec5efddf54cf","title":"Immune environment and antigen specificity of the T cell receptor repertoire of malignant ascites in ovarian cancer","investigator":"Klopp, Ann H.","investigatorInstitution":"Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center","publicationName":"PLOS ONE","researchArea":"Cancer","prettyUrls":{"274":"court-2023-po"},"prettyUrlList":["court-2023-po"],"summary":"We evaluated the association of disease outcome with T cell immune-related characteristics and T cell receptor (TCR) repertoire in malignant ascites from patients with high-grade epithelial ovarian cancer.  Ascitic fluid samples were collected from 47 high-grade epithelial ovarian cancer patients and analyzed using flow cytometry and TCR sequencing to characterize the complementarity determining region 3 TCR β-chain.  TCR functions were analyzed using the McPAS-TCR and VDJ databases.  TCR clustering was implemented using Grouping of Lymphocyte Interactions by Paratope Hotspots software.  Patients with poor prognosis had ascites characterized by an increased ratio of CD8+ T cells to regulatory T cells, which correlated with an increased productive frequency of the top 100 clones and decreased productive entropy.  TCRs enriched in patients with an excellent or good prognosis were more likely to recognize cancer antigens and contained more TCR reads predicted to recognize epithelial ovarian cancer antigens.  In addition, a TCR motif that binds the TP53 neoantigen was identified, and this motif was enriched in patients with an excellent or good prognosis.  Ascitic fluid in high-grade epithelial ovarian cancer patients with an excellent or good prognosis is enriched with TCRs that may recognize ovarian cancer-specific neoantigens, including mutated TP53 and TEAD1.  These results suggest that an effective antigen-specific immune response in ascites is vital for a good outcome in high-grade epithelial ovarian cancer.","prettyUrl":"court-2023-po","following":false,"created":"12/15/2022","featured":false,"publishedDate":"12/15/2022","urlOrId":"court-2023-po","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5c81716a-aab5-496f-9f9c-85e73a82f500","title":"Clonal composition and persistence of antigen-specific circulating T follicular helper cells","investigator":"Sallusto, Federica","investigatorInstitution":"Institute for Research in Biomedicine, Università della Svizzera italiana","publicationName":"European Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"273":"hu-2022-eji"},"prettyUrlList":["hu-2022-eji"],"summary":"T follicular helper (TFH) cells are localized in secondary lymphoid organs and play an essential role in promoting B cell responses and antibody affinity maturation in germinal centres (GC). A subset of memory CD4+ T cells expressing the TFH-signature chemokine receptor CXCR5 has been described in human blood as being phenotypically and clonally related to GC TFH. However, the antigen specificity and the relationship of these circulating TFH (cTFH) cells with other circulating memory CD4+ T cells remain poorly defined. In this study, we combined antigenic stimulation and high-throughput T cell receptor (TCR) Vβ sequencing to define the repertoire of human memory cTFH cells specific for different microbial antigens. We found that CXCR5+ cTFH subsets comprised cells that responded to tetanus toxoid (TT), influenza vaccine (Flu) or Candida albicans (C.alb) but endowed with different effector functions compared to cells in CXCR5– non-cTFH subsets. Interestingly, cTFH and non-cTFH cells specific for C.alb or TT had a largely overlapping TCR Vβ repertoire while the repertoire of cTFH and non-cTFH cells specific for Flu was distinct. Furthermore, in-depth immune phenotyping showed that Flu-specific but not C.alb-specific PD-1+ cTFH cells had a “GC TFH-like” phenotype, with overexpression of IL21, CXCL13, BCL6. Longitudinal analysis of multi-year serial blood donations showed that Flu-specific cTFH and non-cTFH cells persisted as phenotypically stable repertoires for years. Collectively, our study contributes to the understanding of the relationship of cTFH with non-cTFH cells and provide insights on the heterogeneous origin and persistence of human cTFH cells specific for different antigens.","prettyUrl":"hu-2022-eji","following":false,"created":"10/19/2022","featured":false,"publishedDate":"12/05/2022","urlOrId":"hu-2022-eji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"066a7d2f-577d-408f-9e51-5e01589d1dea","title":"T cell repertoire profiling in allografts and native tissues in recipients with COVID-19 after solid organ transplantation: insight into T cell-mediated allograft protection from viral infection","investigator":"Weiner, Joshua","investigatorInstitution":"Columbia University Irving  Medical Center","publicationName":"Frontiers in Immunology","researchArea":"Organ transplant","prettyUrls":{"272":"fu-2022-fi"},"prettyUrlList":["fu-2022-fi"],"summary":"The effects of the SARS-CoV-2 virus on the body, and why the effects are more severe in certain patients, remain incompletely understood. One population of special interest is transplant recipients because of their immunosuppressed state. Understanding the pathophysiology of graft dysfunction in transplant patients with the COVID-19 viral syndrome is important for prognosticating the risk to the graft as well as understanding how best to prevent and, if necessary, treat graft injury in these patients. We analyzed multiple types of solid organ transplant recipients (liver, kidney, heart or lung) at our institution who died from SARS-CoV-2 and underwent autopsy (n = 6) or whose grafts were biopsied during active SARS-CoV-2 infection (n = 8). Their serum inflammatory markers were examined together with the histological appearance, viral load, and TCR repertoire of their graft tissue and, for autopsy patients, several native tissues. Histology and clinical lab results revealed a systemic inflammatory pattern that included elevated inflammatory markers and diffuse tissue damage regardless of graft rejection. Virus was detected throughout all tissues, although most abundant in lungs. The TCR repertoire was broadly similar throughout the tissues of each individual, with greater sharing of dominant clones associated with more rapid disease course. There was no difference in viral load or clonal distribution of overall, COVID-associated, or putative SARS-CoV-2-specific TCRs between allograft and native tissue. We further demonstrated that SARS-CoV-2-specific TCR sequences in transplant patients lack a donor HLA-restricted pattern,\nregardless of distribution in allograft or native tissues, suggesting that recognition of viral antigens on infiltrating recipient cells can effectively trigger host T cell anti-viral responses in both the host and graft. Our findings suggest a systemic immune response to the SARS-CoV-2 virus in solid organ transplant patients that is not associated with rejection and consistent with a largely destructive effect of recipient HLA-restricted T cell clones that affects donor and native organs similarly.","prettyUrl":"fu-2022-fi","following":false,"created":"11/18/2022","featured":false,"publishedDate":"12/01/2022","urlOrId":"fu-2022-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8f249443-8973-4f80-b9fe-5da8fc58796c","title":"Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19","investigator":"Notarangelo, Luigi","investigatorInstitution":"Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health","publicationName":"Nature Medicine","researchArea":"Infectious Disease","prettyUrls":{"271":"sacco-2021-misc"},"prettyUrlList":["sacco-2021-misc"],"summary":"Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.","prettyUrl":"sacco-2021-misc","following":false,"created":"11/02/2022","featured":false,"publishedDate":"11/29/2022","urlOrId":"sacco-2021-misc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ecf9a1fc-611d-47dd-a4ba-31cf541444b3","title":"A TLR7-nanoparticle adjuvant promotes broad immune responses against heterologous strains of Influenza and SARS-CoV-2","investigator":"Pulendran, Bali","investigatorInstitution":"Institute for Immunity, Transplantation and Infection, School of Medicine, Stanford University","publicationName":"Nature Materials","researchArea":"Vaccine efficacy","prettyUrls":{"270":"yin-2022-nm"},"prettyUrlList":["yin-2022-nm"],"summary":"Effective vaccines against viruses such as Influenza and SARS-CoV-2 must elicit a diverse repertoire of antibodies against multiple variant virus strains. However, antibody responses to current vaccines often lack cross-reactivity due to immunodominance. Here, we describe a polymeric toll-like receptor 7 agonist -nanoparticle adjuvant, TLR7-NP, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses.  When mixed with Alum-adsorbed antigens, this TLR7-NP adjuvant elicited cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T cell responses in mice. TLR7-NP adjuvanted influenza subunit vaccine successfully protects mice from heterologous viral challenge. TLR7-NP also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple variants and mobilizes antiviral responses. Moreover, TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve the immune response to viral antigens, with promising implications for vaccine development.","prettyUrl":"yin-2022-nm","following":false,"created":"11/07/2022","featured":false,"publishedDate":"11/22/2022","urlOrId":"yin-2022-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bd1d9a58-8cd6-4ef1-bd67-377d748f3635","title":"Characterization of T Cell Receptor Repertoires in Celiac Disease","investigator":"Bhagat, Govind","investigatorInstitution":"Department of Pathology and Cell Biology, Columbia University","publicationName":"Journal of Clinical Pathology","researchArea":"Gastrointestinal","prettyUrls":{"269":"lee-2022-jcp"},"prettyUrlList":["lee-2022-jcp"],"summary":"Aims: Characterize T-cell receptor gene (TR) repertoires of small intestinal T cells of patients with newly diagnosed (active) celiac disease (ACD), refractory celiac disease type I (RCD I) and CD patients on a gluten-free diet (GFD).\n\nMethods: Next-generation sequencing of complementarity-determining region 3 (CDR3) of rearranged T cell receptor beta (TRB) and gamma (TRG) genes was performed using DNA extracted from intraepithelial cell (IEC) and lamina propria cell (LPC) fractions and a small subset of peripheral blood mononuclear cell (PBMC) samples obtained from CD and non-CD (control) patients. Several parameters were assessed, including relative abundance and enrichment.\n\nResults: TRB and TRG repertoires in CD tissue samples demonstrated lower clonality but higher frequency of rearranged TRs compared to controls. No CD-related differences were detected in the limited number of PBMC samples. Previously published LP gliadin-specific TRB sequences were more frequently detected in LPC samples from CD patients compared to non-CD controls. TRG repertoires of IECs from both ACD and GFD patients demonstrated increased abundance of certain amino acid (AA) motifs compared to controls, encoded by multiple nucleotide variants, including one motif that was enriched in duodenal IECs versus the blood of CD patients.\n\nConclusions: Small intestinal TRB and TRG repertoires of CD patients are more diverse than individuals without CD, likely due to mucosal recruitment and accumulation of T cells because of protracted inflammation. Enrichment of the unique TRG CDR3 AA sequence in the mucosa of CD patients may suggest disease-associated changes in the TCRGD IE lymphocyte (IEL) landscape.","prettyUrl":"lee-2022-jcp","following":false,"created":"09/29/2021","featured":false,"publishedDate":"11/18/2022","urlOrId":"lee-2022-jcp","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"52914af5-01b0-449e-9c6d-a5ee422cb08e","title":"A phase I/Ib trial and analysis of biological correlates of response to neoadjuvant SBRT with single-dose durvalumab in HPV-unrelated locally advanced HNSCC","investigator":"Darragh, Laurel","investigatorInstitution":"Colorado University","publicationName":"Nature Cancer","researchArea":"Cancer Immunotherapy","prettyUrls":{"268":"darragh-2022-nc"},"prettyUrlList":["darragh-2022-nc"],"summary":"Five-year survival for HPV-unrelated head and neck squamous cell carcinomas remains below 50%. We assessed the safety of administering combination hypofractionated stereotactic body radiation therapy (SBRT) with single-dose Durvalumab (anti-PDL-1) neoadjuvantly (n=21) (NCT03635164). The primary endpoint of the study was safety, which was met. Secondary endpoints included radiographic, pathologic, and objective response, locoregional control (LRC), progression-free survival (PFS), and overall survival (OS). Among evaluable patients at an early median follow-up of 16 months (448 days, or 64 weeks), OS was 80.1% with 95% C.I. (62.0%, 100.0%), LRC and PFS were 75.8% with 95% C.I. (57.5%, 99.8%), and major pathological response (MPR) or complete response (CR) was 75% with 95% exact C.I. (51.6%, 100%). Using high-dimensional multi-omics and spatial data as well as biological correlatives, we show that responders had: 1) an increase in effector T cells; 2) a decrease in immunosuppressive cells; and 3) an increase in antigen presentation post-treatment.","prettyUrl":"darragh-2022-nc","following":false,"created":"08/29/2022","featured":false,"publishedDate":"11/02/2022","urlOrId":"darragh-2022-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6a8d5109-613a-4236-9cd1-764a5b2cf049","title":"TCR repertoire analysis of BCMAxCD3 T cell Engagers (TCE)-treated multiple myeloma","investigator":"Friedrich, Mirco Julian","investigatorInstitution":"Broad Institute of Harvard & MIT","publicationName":"Cancer Cell","researchArea":"Cancer Immunotherapy","prettyUrls":{"267":"friedrich-2022-cc"},"prettyUrlList":["friedrich-2022-cc"],"summary":"Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. \n\nHere, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE.","prettyUrl":"friedrich-2022-cc","following":false,"created":"10/26/2022","featured":false,"publishedDate":"10/28/2022","urlOrId":"friedrich-2022-cc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"439be9ea-89b7-4201-8e66-5e526ba0ad30","title":"The ectonucleotidase CD39 identifies tumor- reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer","investigator":"Chow, Andrew","investigatorInstitution":"Memorial Sloan Kettering Cancer Center","publicationName":"Immunity","researchArea":"Cancer","prettyUrls":{"266":"chow-2022-i"},"prettyUrlList":["chow-2022-i"],"summary":"Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer.","prettyUrl":"chow-2022-i","following":false,"created":"10/17/2022","featured":false,"publishedDate":"10/28/2022","urlOrId":"chow-2022-i","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"27a5b01f-0e44-4c70-b5fd-730d60ca7b94","title":"Cetuximab responses in HNSCC patients correlate to clonal expansion feature of peripheral and tumor-infiltrating T cells with top T cell receptor (TCR) clonotypes","investigator":"Ferris, Robert","investigatorInstitution":"UPMC Hillman Cancer Center, Department of Otolaryngology, University of Pittsburg","publicationName":"Clinical Cancer Research","researchArea":"Basic Immunology","prettyUrls":{"265":"ge-2022-ccr"},"prettyUrlList":["ge-2022-ccr"],"summary":"Purpose: Cetuximab is a standard-of-care treatment for head and neck squamous cell carcinoma (HNSCC). Well-defined correlative markers of therapeutic responses are still lacking.  Characterizing dynamic changes of T cell receptor (TCR) repertoire in peripheral blood and tumor tissue may facilitate developing markers for cetuximab response in HNSCCs.\n\nExperimental Design: We analyzed high-throughput TCR sequencing data generated with ImmunoSEQ platform using peripheral blood and tumor infiltrating lymphocytes (TIL) from HNSCC patients before and after cetuximab treatment (pre-/post-PBMC vs. pre-/post-TIL). Multiple analytic approaches were employed to normalize sequencing data.\n\nResults: Normalized TCR richness was significantly lower in post-TIL than pre-TIL, suggesting that cetuximab reduced TCR diversity and promoted TCR expansion in TIL samples, regardless of response status.  The magnitude of clonal expansion (defined as expansion rate) in top-20 TCR clonotypes was significantly higher in responder PBMC with or without normalization, and in responder TIL upon normalization, than non-responder ones.  Notably, the expanded top-20 or top-50 TCR clonotypes overlapped between PBMC and TIL samples, which occurred significantly more frequently in responders than non-responders.\n\nConclusions: Cetuximab-treated HNSCC patients harbor dynamic changes of TCR repertoires correlative to therapeutic responses. The expansion rate of top TCR clonotypes in peripheral blood may serve as a minimally invasive, readily accessible, and feasible marker for predicting cetuximab responses in HNSCCs and beyond, and the expansion rate of top TCR clonotypes in TILs and their overlapping probability between PBMC and TIL may serve as additional predictive markers.  Our study also highlights the importance of data normalization for TCR repertoire analysis.","prettyUrl":"ge-2022-ccr","following":false,"created":"10/12/2022","featured":false,"publishedDate":"10/26/2022","urlOrId":"ge-2022-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"58f80131-b5c4-44cf-b07a-ff75d34ee2f2","title":"T cell receptor repertoires associated with control and disease progression following Mycobacterium tuberculosis infection","investigator":"Scriba, Thomas J.","investigatorInstitution":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town","publicationName":"Nature Medicine","researchArea":"Infectious Disease","prettyUrls":{"264":"musvosvi-2022-nm"},"prettyUrlList":["musvosvi-2022-nm"],"summary":"Antigen-specific, MHC-restricted ab T cells are necessary for protective immunity against Mycobacterium tuberculosis (M.tb), but the ability to broadly study these responses has been limited. Here we used single cell and bulk TCR sequencing and the GLIPH2 algorithm to analyze millions of M.tb-specific sequences in two longitudinal cohorts, comprising 166 individuals with M.tb infection who either progressed to tuberculosis (N = 48) or controlled infection (N = 118). We found 24 T cell groups with similar TCRb sequences, predicted by GLIPH2 to have common TCR specificities, which associated with control of infection, and others that associated with progression to disease. Using a genome-wide M.tb antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered high-priority targets for future vaccine development.","prettyUrl":"musvosvi-2022-nm","following":false,"created":"10/17/2022","featured":false,"publishedDate":"10/20/2022","urlOrId":"musvosvi-2022-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"cf68c71a-abd0-452a-b036-7a052a907a5a","title":"Selective retention of virus-specific tissue-resident T cells in healed skin after recovery from herpes zoster","investigator":"Laing, Kerry J","investigatorInstitution":"Department of Medicine, University of Washington","publicationName":"Nature Communications","researchArea":"Infectious Disease","prettyUrls":{"263":"laing-2022-nc"},"prettyUrlList":["laing-2022-nc"],"summary":"Herpes zoster is a localized skin infection caused by reactivation of latent varicella-zoster virus. Tissue-resident T cells likely control skin infections. Zoster provides a unique opportunity to determine if focal reinfection of human skin boosts local or disseminated antigen-specific tissue-resident T cells. Here, we show virus-specific T cells are retained over one year in serial samples of rash site and contralateral unaffected skin of individuals recovered from zoster. Consistent with zoster resolution, viral DNA is largely undetectable on skin from day 90 and virus-specific B and T cells decline in blood. In skin, there is selective infiltration and long-term persistence of varicella-zoster virus-specific T cells in the rash site relative to the contralateral site. The skin T cell infiltrates express the canonical tissue-resident T cell markers CD69 and CD103. These findings show that zoster promotes spatially-restricted long-term retention of antigen-specific tissue-resident T cells in previously infected skin.","prettyUrl":"laing-2022-nc","following":false,"created":"07/21/2022","featured":false,"publishedDate":"09/29/2022","urlOrId":"laing-2022-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"41ccd59e-b478-499e-bb7e-e03cfa88b76f","title":"Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients","investigator":"Brisotto, Giulia","investigatorInstitution":"Immunopathology and Cancer Biomarkers Units, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO)","publicationName":"Frontiers in Oncology","researchArea":"Cancer","prettyUrls":{"262":"muraro-2022-fo"},"prettyUrlList":["muraro-2022-fo"],"summary":"Background: Metastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC.\nMethods: A cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method.\nResults: Stratifying patients for their prognostic level of 6 CTCs  before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03). \nConclusion: These data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers.","prettyUrl":"muraro-2022-fo","following":false,"created":"08/04/2022","featured":false,"publishedDate":"09/20/2022","urlOrId":"muraro-2022-fo","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"0e747ae4-093a-4754-bd7b-c0cd31f8b3f7","title":"T Cell Receptor Sequencing Reveals Reduced Clonal Breadth of T Cell Responses against SARS-CoV-2 after Natural Infection and Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Recipients","investigator":"Simonetta, Federico","investigatorInstitution":"Geneva University Hospitals and University of Geneva , Division of Hematology, Department of Oncology","publicationName":"Annals of Oncology","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"261":"pradier-2022-ao"},"prettyUrlList":["pradier-2022-ao"],"summary":"Allogeneic hematopoietic stem cell transplantation (HSCT) is still associated with significant morbidity and mortality related to infectious complications, with viral infections being the most frequent infectious events. Allogenic HSCT recipients have a higher risk to develop severe forms of COVID-19 and a higher mortality rate after infection with SARS-CoV2 compared to the general population. Prevention by vaccination is critically important in allogeneic HSCT recipients but impaired humoral and cellular responses have been reported. To gain further insights into the immune defects leading to impaired immune responses to SARS-CoV-2 in allogeneic HSCT recipients we performed high-throughput T cell receptor (TCR) repertoire profiling of cells recovered from allogeneic HSCT recipients or healthy controls after SARS-CoV2 natural infection or mRNA-based vaccination. \nSARS-CoV-2- specific T cell clonotypes were detectable in both HC (n=10) and HSCT (n=11) recipients after COVID-19 infection. However, HSCT recipients displayed significantly reduced SARS-CoV-2-specific T cell clonotypes and a less diverse TCR repertoire, as revealed by higher Simpson clonality, compared with HC. Performing the same analysis on samples recovered from allogeneic HSCT recipients (n=11) or from healthy controls (n=10) after vaccination with 3 doses of mRNA-based SARS-CoV-2 vaccines, we observed a significant reduction in S-protein-specific T cell clonotypes in allogeneic HSCT recipient compared to HC. We detected a significant negative correlation between the Simpson clonality and the number of SARS-CoV-2-specific T cell clonotypes following natural infection or vaccination.\nOur results indicate that allogeneic HSCT recipients display a defect in cellular SARS-CoV-2-specific responses after COVID-19 infection and vaccination. Such impairment was associated with increased T-cell clonality after HSCT, pointing to the reduced diversity of the TCR repertoire as a mechanism leading to impaired cellular responses against SARS-CoV-2 in HSCT recipients. SARS-CoV-2 infection represents an unprecedented opportunity to study the immune responses established in allogeneic HSCT recipients against a new pathogen that either the donor or the HSCT recipient have never been exposed to. Our findings provide insights into our understanding of immune-dysfunction after allogeneic HSCT.","prettyUrl":"pradier-2022-ao","following":false,"created":"08/30/2022","featured":false,"publishedDate":"09/16/2022","urlOrId":"pradier-2022-ao","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a0151bae-347f-4fa6-9e8d-252733f8b6cb","title":"Evolution and modulation of antigen-specific T cell responses in melanoma patients","investigator":"Huuhtanen, Jani","investigatorInstitution":"Hematology Research Unit Helsinki, University of Helsinki","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"260":"huuhtanen-2022-nc"},"prettyUrlList":["huuhtanen-2022-nc"],"summary":"Analyzing antigen-specific T cell responses at scale has been challenging. Here, we analyze three types of T cell receptor (TCR) repertoire data (antigen-specific TCRs, TCR-repertoire, and single-cell RNA+TCRαβ-sequencing data) from 515 patients with primary or metastatic melanoma and compare it to 783 healthy controls. Although melanoma-associated antigen (MAA) -specific TCRs are restricted to individuals, they share sequence similarities that allow us to build classifiers for predicting anti-MAA T cells. The frequency of anti-MAA T cells distinguishes melanoma patients from healthy and predicts metastatic recurrence from primary melanoma. Anti-MAA T cells have stem-like properties and frequent interactions with regulatory T cells and tumor cells via Galectin9-TIM3 and PVR-TIGIT -axes, respectively. In the responding patients, the number of expanded anti-MAA clones are higher after the anti-PD1(+anti-CTLA4) therapy and the exhaustion phenotype is rescued. Our systems immunology approach paves the way for understanding antigen-specific responses in human disorders.","prettyUrl":"huuhtanen-2022-nc","following":false,"created":"08/23/2022","featured":false,"publishedDate":"09/12/2022","urlOrId":"huuhtanen-2022-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f29f5aa5-f20a-404f-901d-bf29d8ab1bf1","title":"Siglec-7 represents a glyco-immune checkpoint for non-exhausted effector memory CD8+ T cells with high functional and metabolic capacities","investigator":"von Guten, Stephan","investigatorInstitution":"Institute of Pharmacology, University of Bern","publicationName":"Frontiers in Immunology","researchArea":"Basic Immunology","prettyUrls":{"259":"haas-2022-fi"},"prettyUrlList":["haas-2022-fi"],"summary":"While inhibitory Siglec receptors are known to regulate myeloid cells, less is known about their expression and function in lymphocytes subsets. Here we identified Siglec-7 as a lycol-immune checkpoint expressed on non-exhausted effector memory CD8+ T cells that exhibit high functional and metabolic capacities. Seahorse analysis revealed higher basal respiration and glycolysis levels of Siglec-7+ CD8+ T cells in steady state, and particularly upon activation. Siglec-7 polarization into the T cell immune synapse was dependent on sialoglycan interactions in trans and prevented actin polarization and effective T cell responses. Siglec-7 ligands were found to be expressed on both leukemic stem cells and acute myeloid leukemia (AML) cells suggesting the occurrence of lycol-immune checkpoints for Siglec-7+ CD8+ T cells, which were found in patients’ peripheral blood and bone marrow. Our findings project Siglec-7 as a lycol-immune checkpoint and therapeutic target for T cell-driven disorders and cancer.","prettyUrl":"haas-2022-fi","following":false,"created":"08/19/2022","featured":false,"publishedDate":"09/06/2022","urlOrId":"haas-2022-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4971360b-869c-45e5-9364-1f6cecce1355","title":"Anti-spike T-cell and Antibody Responses to SARS-CoV-2 mRNA Vaccines in Patients with Hematologic Malignancies","investigator":"Greenberger, Lee M","investigatorInstitution":"The Leukemia & Lymphoma Society","publicationName":"Blood Cancer Discovery","researchArea":"Infectious Disease","prettyUrls":{"258":"greenberger-2022-bcd"},"prettyUrlList":["greenberger-2022-bcd"],"summary":"The anti-spike T-cell and antibody responses to SARS-CoV-2 mRNA vaccines in patients with B-cell malignancies were examined in a real-world setting. A next-generation sequencing (NGS)-based molecular assay was used to assess SARS-CoV-2-specific T-cell responses. After the second dose, 58% (166/284) of seropositive and 45% (99/221) of seronegative patients display anti-spike T cells. The percentage of patients who displayed T-cell response was higher among patients receiving mRNA-1273 vaccines compared with those receiving BNT162b2 vaccines. After the third vaccination, 40% (137/342) of patients seroconverted, although only 22% displayed sufficient antibody levels associated with the production of neutralizing antibodies. 97% (717/738) of patients who were seropositive before the third dose had markedly elevated anti-spike antibody levels. Anti-spike antibody levels, but not T-cell responses, were depressed by B cell-directed therapies. Vaccinated patients with B-cell malignancies with a poor response to SARS-CoV-2 vaccines may remain vulnerable to COVID-19 infections.","prettyUrl":"greenberger-2022-bcd","following":false,"created":"08/23/2022","featured":false,"publishedDate":"09/02/2022","urlOrId":"greenberger-2022-bcd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b1a51655-6b1a-4eb2-a349-2aeba44863b0","title":"SARS-CoV-2-Specific T Cell Responses in Patients with Multisystem Inflammatory Syndrome in Children","investigator":"Henderson, Lauren A","investigatorInstitution":"Division of Immunology, Boston Children’s Hospital, Harvard Medical School","publicationName":"Clinical Immunology","researchArea":"Infectious Disease","prettyUrls":{"257":"lam-2022-ci"},"prettyUrlList":["lam-2022-ci"],"summary":"Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vβ skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vβ11-2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.","prettyUrl":"lam-2022-ci","following":false,"created":"08/30/2022","featured":false,"publishedDate":"08/30/2022","urlOrId":"lam-2022-ci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"804308d7-33d4-4017-a125-8d77143998d9","title":"Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade","investigator":"Flatz, Lukas","investigatorInstitution":"Department of Dermatology, University Hospital Tübingen","publicationName":"Science Immunology","researchArea":"Cancer Immunotherapy","prettyUrls":{"256":"berner-2022-si"},"prettyUrlList":["berner-2022-si"],"summary":"Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8+ T cell responses, with ICB responders harboring higher frequencies of these CD8+ T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8+ T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.","prettyUrl":"berner-2022-si","following":false,"created":"08/08/2022","featured":false,"publishedDate":"08/11/2022","urlOrId":"berner-2022-si","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5d8d03a1-b6e5-44d6-b939-81e1bf36e29c","title":"Temporal development of T cell receptor repertoires during childhood in health and disease","investigator":"MIchels, Aaron W.","investigatorInstitution":"Barbara Davis Center for Diabetes, University of Colorado School of Medicine","publicationName":"JCI Insight","researchArea":"Basic Immunology","prettyUrls":{"255":"mitchell-2022-jcii"},"prettyUrlList":["mitchell-2022-jcii"],"summary":"T cell receptor (TCR) sequences are exceptionally diverse and can now be comprehensively measured with next generation sequencing technologies. However, a thorough investigation of longitudinal TCR repertoires throughout childhood in health and during development of a common childhood disease, type 1 diabetes (T1D), has not been undertaken. Here, we deep-sequenced the TCR beta chain (TCRβ) repertoires from longitudinal peripheral blood DNA samples at four time points beginning early in life (median age of 1.4 years) from children that progressed to T1D (n=29) and age/sex-matched islet autoantibody negative controls (n=25). From 53 million TCRβ sequences, we show that the repertoire is extraordinarily diverse early in life and narrows with age independent of disease. We demonstrate the ability to identify specific TCR sequences, including those known to recognize influenza A and separately those specific for insulin and its precursor, preproinsulin. Insulin-reactive TCRβ sequences are more common and frequent in number as the disease progressed in those who developed T1D compared to genetically at-risk non-diabetic children, which was not the case for influenza-reactive sequences. As an independent validation, we sequenced and analyzed TCRβ repertoires from a cohort of new-onset T1D patients (n=143), identifying the same preproinsulin-reactive TCRs. These results demonstrate an enrichment of preproinsulin-reactive TCR sequences during the progression to T1D, highlighting the importance of using disease-relevant TCR sequences as powerful biomarkers in autoimmune disorders.","prettyUrl":"mitchell-2022-jcii","following":false,"created":"06/15/2022","featured":false,"publishedDate":"07/14/2022","urlOrId":"mitchell-2022-jcii","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ab25f2b3-f385-4668-9e6c-6369f12c907e","title":"Single-cell profiling of the leukemic and non-leukemic immune cell compartments in CD8+ T-cell Large Granular Lymphocytic Leukemia","investigator":"Huuhtanen, Jani","investigatorInstitution":"Hematology Research Unit Helsinki, University of Helsinki","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"254":"huuhtanen-2021-nc"},"prettyUrlList":["huuhtanen-2021-nc"],"summary":"T-cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T-cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T-cell response to an antigen, the role of the non-leukemic immune system in this response is largely uncharacterized. By utilizing single-cell RNA and T-cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes. In addition, T-LGLL clonotypes show more active cell communication than reactive clones with non-leukemic immune cells via costimulatory cell–cell interactions, monocyte-secreted proinflammatory cytokines, and T-LGLL-clone-secreted IFNγ. Besides the leukemic repertoire, the non-leukemic T-cell repertoire in T-LGLL is also more mature, cytotoxic, and clonally restricted than in other cancers and autoimmune disorders. Finally, 67% of the leukemic T-LGLL clonotypes share T-cell receptor similarities with their non-leukemic repertoire, linking the leukemic and non-leukemic repertoires together via possible common target antigens. Our results provide a rationale to prioritize therapies that target the entire immune repertoire and not only the T-LGLL clonotype.","prettyUrl":"huuhtanen-2021-nc","following":false,"created":"10/08/2021","featured":false,"publishedDate":"05/23/2022","urlOrId":"huuhtanen-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"194fcf49-c500-41ea-addb-0207581af787","title":"Systemic Inflammation and Tumour-Infiltrating T-Cell Receptor Repertoire Diversity Are Predictive of Clinical Outcome in High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements","investigator":"Gebauer, Niklas","investigatorInstitution":"Department of Haematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck","publicationName":"Cancers","researchArea":"Cancer","prettyUrls":{"253":"olschewski-2021-c"},"prettyUrlList":["olschewski-2021-c"],"summary":"High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (double/triple-hit high grade B-cell lymphoma, HGBL-DH/TH) constitutes a provisional entity among B-cell malignancies with an aggressive behavior and dire prognosis. While evidence for the essential prognostic role of the composition of the tumor-microenvironment (TME) in hematologic malignancies is growing, its prognostic impact in HGBL-DH/TH remains unknown. In this study, we outline the adaptive immune response in a cohort of 47 HGBL-DH/TH and 27 triple-negative diffuse large B-cell lymphoma (tnDLBCL) patients in a large-scale, next-generation sequencing (NGS) investigation of the T-cell receptor (TCR) β-chain repertoire and supplement our findings with data on the Glasgow-Prognostic Score (GPS) at diagnosis, as a score-derived measure of systemic inflammation. We supplement these studies with an immunophenotypic investigation of the TME. Our findings demonstrate that the clonal architecture of the TCR repertoire of HGBL-DH/TH differs significantly from tnDLBCL. Moreover, several entity-exclusive clonotypes, suggestive of tumor-neoantigen selection are identified. Additionally, both productive clonality and percentage of maximum frequency clone as measures of TCR repertoire diversity and tumor-directed activity of the adaptive immune system had significant impact on overall survival (OS; productive clonality: p = 0.0273; HR: 2.839; CI: 1.124-7.169; maximum productive frequency: p = 0.0307; HR: 2.167; CI: 1.074-4.370) but not PFS (productive clonality: p = 0.4459; maximum productive frequency: p = 0.5567) in HGBL-DH/TH patients, while GPS was a significant predictor of both OS and PFS (OS: p < 0.0001; PFS: p = 0.0002). Subsequent multivariate analysis revealed GPS and the revised international prognostic index (R-IPI) to be the only prognosticators holding significant impact for OS (GPS: p = 0.038; R-IPI: p = 0.006) and PFS (GPS: p = 0.029; R-IPI: p = 0.006) in HGBL-DH/TH. Through the identification of expanded, recurrent and entity-exclusive TCR-clonotypes we provide indications for a distinct subset of tumor-neoantigenic elements exclusively shared among HGBL-DH/TH. Further, we demonstrate an adverse prognostic role for both systemic inflammation and uniform adaptive immune response.","prettyUrl":"olschewski-2021-c","following":false,"created":"05/20/2022","featured":false,"publishedDate":"05/20/2022","urlOrId":"olschewski-2021-c","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4ae9ad1c-de36-4acf-80ce-9e799d79abe0","title":"SARS-CoV-2 vaccination diversifies the CD4+ T cell repertoire in patients with prior SARS-CoV-2 infection","investigator":"Smith, Kellie N.","investigatorInstitution":"Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University","publicationName":"EBioMedicine","researchArea":"Vaccine efficacy","prettyUrls":{"252":"dykema-2022-ebiomed"},"prettyUrlList":["dykema-2022-ebiomed"],"summary":"COVID-19 mRNA vaccines elicit strong T and B cell responses to the SARS-CoV-2 spike glycoprotein in both SARS-CoV-2 naïve and experienced patients. However, it is unknown whether the post-vaccine CD4+ T cell boost, critical for virus-specific immune memory, seen in patients with a history of COVID-19 is due to restimulation of T cell clonotypes that were first activated during SARS-CoV-2 primary infection or is the result of new clones that are activated by the vaccine. We identified both new and preexisting T cell receptor clonotypes and found that vaccination significantly broadens the SARS-CoV-2-reactive CD4+ T cell repertoire in patients with a history of COVID-19. Additionally, we demonstrated that the vaccine preferentially induces T cells that only recognize SARS-CoV-2 antigens, rather than the less-avid SARS-CoV-2/common cold coronavirus (CCC) cross-reactive responses. These data demonstrate that SARS-CoV-2 vaccination induces a distinct antigen-specific repertoire relative to natural infection and increases the breadth of the SARS-CoV-2-reactive T cell response.","prettyUrl":"dykema-2022-ebiomed","following":false,"created":"08/17/2021","featured":false,"publishedDate":"05/20/2022","urlOrId":"dykema-2022-ebiomed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9901707c-4881-4543-b0da-6167ed370e6b","title":"Longitudinal analysis of T-cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection","investigator":"Tonon, Giovanni","investigatorInstitution":"IRCCS Ospedale San Raffaele","publicationName":"Journal of Clinical Investigation","researchArea":"Infectious Disease","prettyUrls":{"251":"gittelman-2022-jci"},"prettyUrlList":["gittelman-2022-jci"],"summary":"T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo’, Italy conducted after the initial SARS-CoV-2 outbreak, we sampled the T-cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At two months, we found that 97.0% (98/101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T-cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78/96) and 86.2% (25/29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.","prettyUrl":"gittelman-2022-jci","following":false,"created":"05/05/2022","featured":false,"publishedDate":"05/16/2022","urlOrId":"gittelman-2022-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1f83aaee-5801-4264-bbae-45d3b56e4904","title":"Microenvironmental correlates of immune checkpoint inhibitor response in human melanoma brain metastases revealed by T cell receptor and single-cell RNA sequencing","investigator":"Brastianos, Priscilla","investigatorInstitution":"Massachusetts General Hospital","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"250":"alvarez-breckenridge-2022-cir"},"prettyUrlList":["alvarez-breckenridge-2022-cir"],"summary":"Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 27 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.","prettyUrl":"alvarez-breckenridge-2022-cir","following":false,"created":"03/19/2022","featured":false,"publishedDate":"05/04/2022","urlOrId":"alvarez-breckenridge-2022-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9b5be686-453e-4dc1-af85-517d4a5085af","title":"T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity","investigator":"Koelle, David M","investigatorInstitution":"University of Washington","publicationName":"JCI insight","researchArea":"Infectious Disease","prettyUrls":{"249":"elyanow-2022-jci"},"prettyUrlList":["elyanow-2022-jci"],"summary":"BACKGROUND. Measuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T-cell responses, but these responses vary with disease severity and individual characteristics.\n  \nMETHODS. A T-cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T-cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T-cell testing was assessed and compared to serologic testing.\n\nRESULTS. SARS-CoV-2–specific T-cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T-cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T-cell testing was most apparent in recovered, non-hospitalized individuals sampled >150 days after initial illness, suggesting greater sensitivity than serology at later timepoints and in individuals with less severe disease. T-cell testing identified SARS-CoV-2 infection in 68% (55/81) of samples with undetectable nAb titers (<1:40) and in 37% (13/35) of samples negative by 3 antibody assays. \n\nCONCLUSION. These results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.","prettyUrl":"elyanow-2022-jci","following":false,"created":"03/31/2022","featured":false,"publishedDate":"04/20/2022","urlOrId":"elyanow-2022-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c06842c7-aab0-4cf7-a298-44745cbea263","title":"PD-1 and ICOS co-expression identifies tumor-reactive CD4 T cells in human solid tumors","investigator":"Duhen, Thomas","investigatorInstitution":"Earle A. Chiles Research Institute, Providence Cancer Institute","publicationName":"Journal of Clinical Investigation","researchArea":"Cancer Immunotherapy","prettyUrls":{"248":"duhen-2022-jci"},"prettyUrlList":["duhen-2022-jci"],"summary":"CD4 T helper (Th) cells play a key role in orchestrating immune responses, but the identity of the CD4 Th cells involved in the anti-tumor immune response remains to be defined. We analyzed the immune cell infiltrates of head and neck squamous cell carcinoma and colorectal cancers and identified a subset of CD4 Th cells distinct from FOXP3+ regulatory T cells that co-expressed PD-1 and ICOS. These tumor-infiltrating CD4 Th cells (CD4 Th TIL) had a tissue-resident memory phenotype, were present in MHC class II-rich areas and proliferated in the tumor suggesting local antigen recognition. The T-cell receptor repertoire of the PD-1+ICOS+ CD4 Th TIL was oligoclonal, with T-cell clones expanded in the tumor, but present at low frequencies in the periphery. Finally, these PD-1+ICOS+ CD4 Th TIL were shown to recognize both tumor-associated antigens and tumor-specific neoantigens. Our findings provide an approach for isolating tumor-reactive CD4 Th TIL directly ex vivo that will help define their role in the anti-tumor immune response and potentially improve future adoptive T-cell therapy approaches.","prettyUrl":"duhen-2022-jci","following":false,"created":"04/18/2022","featured":false,"publishedDate":"04/19/2022","urlOrId":"duhen-2022-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6c8696a8-e811-4029-a840-88ca2362a974","title":"Neoantigen specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function","investigator":"Veatch, Joshua","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Cancer Cell","researchArea":"Cancer","prettyUrls":{"247":"veatch-2022-cc"},"prettyUrlList":["veatch-2022-cc"],"summary":"CD4+ T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4+ T cells infiltrating human melanoma. Conventional CD4+ T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ. The frequency of CXCL13+ CD4+ T cells in the tumor correlated with the transcriptional states of CD8+ T cells and macrophages, maturation of B cells, and patient survival. Similar correlations were observed in a breast cancer cohort. These results identify phenotypes and functional correlates of tumor-specific CD4+ T cells in melanoma and suggest the possibility of using such cells to modify the tumor microenvironment.","prettyUrl":"veatch-2022-cc","following":false,"created":"03/03/2022","featured":false,"publishedDate":"04/18/2022","urlOrId":"veatch-2022-cc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3e202bcc-f154-4d79-9f7b-f0524fbc1296","title":"Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients","investigator":"Ollert, Marcus","investigatorInstitution":"Department of Infection and Immunity, Luxembourg Institute of Health (LIH)","publicationName":"Cell Reports Medicine","researchArea":"Infectious Disease","prettyUrls":{"246":"capelle-2022-crm"},"prettyUrlList":["capelle-2022-crm"],"summary":"While immunopathology has been widely studied in patients with severe COVID-19, immune responses in non-hospitalized patients have remained largely elusive. We systematically analyze 484 peripheral cellular or soluble immune features in a longitudinal cohort of 63 mild and 15 hospitalized patients versus 14 asymptomatic and 26 household controls. We observe a transient increase of IP10/CXCL10 and interferon-β levels, coordinated responses of dominant SARS-CoV-2-specific CD4 and fewer CD8 T cells, and various antigen-presenting and antibody-secreting cells in mild patients within 3 days of PCR diagnosis. The frequency of key innate immune cells and their functional marker expression are impaired in hospitalized patients at day 1 of inclusion. T cell and dendritic cell responses at day 1 are highly predictive for SARS-CoV-2-specific antibody responses after 3 weeks in mild but not hospitalized patients. Our systematic analysis reveals a combinatorial picture and trajectory of various arms of the highly coordinated early-stage immune responses in mild COVID-19 patients.","prettyUrl":"capelle-2022-crm","following":false,"created":"03/15/2022","featured":false,"publishedDate":"04/01/2022","urlOrId":"capelle-2022-crm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"284b2fdc-fc90-4c4e-9807-c248629990eb","title":"Durable expansion of TCR-δ meta-clonotypes after BCG revaccination in humans","investigator":"Seshadri, Chetan","investigatorInstitution":"Department of Medicine, University of Washington","publicationName":"Frontiers in Immunology","researchArea":"Response to Therapeutic Agent","prettyUrls":{"245":"james-2022-fi"},"prettyUrlList":["james-2022-fi"],"summary":"Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for 100 years and prevents disseminated tuberculosis and death in young children. However, it shows only partial efficacy against pulmonary tuberculosis (TB) in adults, so new vaccines are urgently needed. The protective efficacy of BCG depends on T cells, which are typically activated by pathogen-derived protein antigens that bind to highly polymorphic major histocompatibility complex (MHC) molecules. Some T cells recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. Whether live whole cell vaccines, like BCG, can induce durable expansions of DURT cells in humans is not known. We used combinatorial tetramer staining, multi-parameter flow cytometry, and immunosequencing to comprehensively characterize the effect of BCG on activation and expansion of DURT cell subsets. We examined peripheral blood mononuclear cells (PBMC) derived from a Phase I study of South African adults in which samples were archived at baseline, 3 weeks, and 52 weeks post-BCG revaccination. We did not observe a change in the frequency of total mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or  T cells at 52 weeks post-BCG. However, immunosequencing revealed a set of TCR- clonotypes that were expanded at 52 weeks post-BCG revaccination. These expanded clones expressed the V2 gene segment and could be further defined on the basis of biochemical similarity into several ‘meta-clonotypes’ that likely recognize similar epitopes. Our data reveal that BCG vaccination leads to durable expansion of DURT cell clonotypes despite a limited effect on total circulating frequencies in the blood and have implications for defining the immunogenicity of candidate whole cell TB vaccines.","prettyUrl":"james-2022-fi","following":false,"created":"03/10/2022","featured":false,"publishedDate":"03/23/2022","urlOrId":"james-2022-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"aaac6745-68ef-437d-bca1-8ccd57d4ec87","title":"Serial analysis of the T-cell repertoire in people living with HIV+ defines the limited impact of long-term anti-retroviral therapy","investigator":"Towlerton, Andrea MH","investigatorInstitution":"Clinical Research Division, Fred Hutchinson Cancer Research Center","publicationName":"Frontiers in Immunology","researchArea":"HIV","prettyUrls":{"244":"towlerton-2022-hiv"},"prettyUrlList":["towlerton-2022-hiv"],"summary":"Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4+ T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor β-chain (TRB) repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the TRB repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis. TRB repertoires were characterized via high-throughput sequencing of the TRB variable region performed on genomic DNA extracted from unsorted peripheral blood mononuclear cells. Additional laboratory and clinical metadata including serial measurements of HIV viral load and CD4 + T-cell count were available for all individuals in the cohort. A previously published control group of 189 TRB repertoires from peripheral blood samples of adult bone marrow transplant donors was evaluated for comparison. ART initiation in PLHIV was associated with a sustained reduction in viral load and a significant increase in TRB repertoire diversity. However, repertoire diversity in PLHIV remained significantly lower than in the control group even after long-term ART. The composition of TRB repertoires of PLHIV after ART also remained perturbed compared to the control cohort, as evidenced by large persistent private clonal expansions, reduced efficiency in the generation of TRB CDR3 amino acid sequences, and a narrower range of CDR3 lengths. Network analysis revealed an antigen-experienced structure in the TRB repertoire of PLHIV both before and after ART initiation that was quite distinct from the structure of control repertoires, with a slight shift toward a more naïve structure observed after ART initiation. Though we observe significant improvement in TRB repertoire diversity with durable viral suppression in PLHIV on long-term ART, the composition and structure of these repertoires remain significantly perturbed compared to the control cohort of adult bone marrow transplant donors.","prettyUrl":"towlerton-2022-hiv","following":false,"created":"02/18/2022","featured":false,"publishedDate":"03/03/2022","urlOrId":"towlerton-2022-hiv","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d1558b60-30a4-4f50-bbea-cc3a63805d42","title":"Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia","investigator":"Bhattacharya, Dipabarna","investigatorInstitution":"Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center","publicationName":"Blood Cancer Journal","researchArea":"Cancer","prettyUrls":{"243":"bhattacharya-2022-bcj"},"prettyUrlList":["bhattacharya-2022-bcj"],"summary":"CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E). Multiple STAT5B mutations were present in 22% (5/23) of STAT5B mutated CD4+ T-LGLL cases, either coexisting in one clone or in distinct clones. Patients with STAT5B mutations had increased lymphocyte and LGL counts when compared to STAT5B wild-type patients. TCRβ sequencing showed that, in addition to large LGL expansions, non-leukemic T cell repertoires were more clonal in CD4+ T-LGLL compared to healthy. Interestingly, 25% (15/59) of CD4+ T-LGLL clonotypes were found, albeit in much lower frequencies, in the non-leukemic CD4+ T cell repertoires of the CD4+ T-LGLL patients. Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.","prettyUrl":"bhattacharya-2022-bcj","following":false,"created":"01/12/2022","featured":false,"publishedDate":"02/24/2022","urlOrId":"bhattacharya-2022-bcj","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"880b7ad2-1587-492d-9444-d4366ec71d31","title":"ATR-mediated CD47 and PD-L1 upregulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer","investigator":"Hsieh, Rodney Cheng-En","investigatorInstitution":"Department of Immunology, The University of Texas MD Anderson Cancer Center","publicationName":"Science Immunology","researchArea":"Cancer","prettyUrls":{"242":"hsieh-2022-si"},"prettyUrlList":["hsieh-2022-si"],"summary":"Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.","prettyUrl":"hsieh-2022-si","following":false,"created":"02/24/2022","featured":false,"publishedDate":"02/24/2022","urlOrId":"hsieh-2022-si","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1d60516a-ac87-4d5b-8685-fb31d5aa2f5a","title":"Evidence of SARS-CoV-2-specific T-cell-mediated myocarditis in a MIS-A case","investigator":"Vannella, Kevin M.","investigatorInstitution":"Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health","publicationName":"Frontiers in Immunology","researchArea":"Other","prettyUrls":{"240":"vannella-2021-fi"},"prettyUrlList":["vannella-2021-fi"],"summary":"A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.","prettyUrl":"vannella-2021-fi","following":false,"created":"11/05/2021","featured":false,"publishedDate":"02/18/2022","urlOrId":"vannella-2021-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c6bbe2b1-a828-4df6-9c51-1dd37aff0525","title":"SARS-CoV-2 (COVID-19)-specific T-cell and B-cell responses in convalescent rheumatoid arthritis: monozygotic twins pair case observation","investigator":"Arruda, Lucas CM","investigatorInstitution":"Department of Clinical Science, Intervention and Technology, Karolinska Institute","publicationName":"Scandinavian Journal of Immunology","researchArea":"RA","prettyUrls":{"239":"arruda-2022-sji"},"prettyUrlList":["arruda-2022-sji"],"summary":"Rheumatoid arthritis (RA) patients present higher risk of SARS-CoV-2 infection (COVID-19), and proper management of the disease in this population requires a better understanding of how the immune system controls the virus. We analyzed the T cell and B cell phenotypes, and their repertoire in a pair of monozygotic twins with RA mismatched for COVID-19 infection. Twin- was not infected, while Twin+ was infected and effectively controlled the infection. We found no significant changes on the αβ T cell composition, while γδ T cells and B cells presented considerable expansion of memory population in Twin+ and robust T/B cell responses to several SARS-CoV-2 peptides. T cell receptor β/γ-chain and immunoglobulin heavy chain next-generation sequencing depicted a remarkable higher diversity in Twin+ compared with Twin-, despite no significant changes being found in variable/joining family usage. Repertoire overlap analyses showed that, although being identical twins, very few clones were shared between them, indicating that COVID-19 may lead to deep changes on the immune cell repertoire in RA patients. Altogether, our results indicate that RA patients may develop robust and persistent COVID-19-specific T/B cell responses; γδ T cells and B cells may play a key role in the management of COVID-19 in RA, and the infection may lead to a profound reshaping of immune cell receptor specificities.","prettyUrl":"arruda-2022-sji","following":false,"created":"02/15/2022","featured":false,"publishedDate":"02/15/2022","urlOrId":"arruda-2022-sji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b3c01fd5-b111-4ec5-a4cb-88ad60618be8","title":"Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse","investigator":"DeWolf, Susan","investigatorInstitution":"Memorial Sloan Kettering Cancer Center","publicationName":"Science Translational Medicine","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"238":"dewolf-2022-gvhd"},"prettyUrlList":["dewolf-2022-gvhd"],"summary":"T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.","prettyUrl":"dewolf-2022-gvhd","following":false,"created":"02/01/2022","featured":false,"publishedDate":"02/02/2022","urlOrId":"dewolf-2022-gvhd","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b81d545a-b051-4933-9a63-cc1a856663f6","title":"Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells","investigator":"Yeh, Chen-Hao","investigatorInstitution":"Department of Immunology","publicationName":"Immunity","researchArea":"Basic Immunology","prettyUrls":{"237":"yeh-2021-immunity"},"prettyUrlList":["yeh-2021-immunity"],"summary":"T follicular helper (Tfh) cells are defined by a Bcl6+CXCR5hiPD-1hi phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90neg/lo GCTfh cells required antigen-specific, MHCII+ B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90hi Tfh (GCTfh-like) cells developed normally in the absence of MHCII+ B cells and proliferated continu- ously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90hi GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90neg/lo and CD90hi GCTfh-like cells were enriched in different functional pathways. Thus, GC- resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.","prettyUrl":"yeh-2021-immunity","following":false,"created":"01/25/2022","featured":false,"publishedDate":"01/25/2022","urlOrId":"yeh-2021-immunity","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"807cb88d-294a-4ce8-a39e-453ab391eea6","title":"DJ-1 depletion prevents immunoaging in T-cell compartments","investigator":"Hefeng, Feng","investigatorInstitution":"Department of Infection and Immunity","publicationName":"EMBO Reports","researchArea":"Immunosenescence","prettyUrls":{"236":"zeng-2022-embor"},"prettyUrlList":["zeng-2022-embor"],"summary":"Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.","prettyUrl":"zeng-2022-embor","following":false,"created":"01/05/2022","featured":false,"publishedDate":"01/17/2022","urlOrId":"zeng-2022-embor","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"978766f4-ea28-4961-a052-1469328d3073","title":"Expansion of Candidate HPV-specific T Cells in the Tumor Microenvironment During Chemoradiotherapy is Prognostic in HPV16+ Cancers","investigator":"Colbert, Lauren E.","investigatorInstitution":"Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"235":"colbert-2022-cir"},"prettyUrlList":["colbert-2022-cir"],"summary":"Human papillomavirus (HPV) infection causes 600,000 new cancers worldwide each year. HPV-related cancers express the oncogenic proteins E6 and E7, which could serve as tumor-specific antigens. It is not known whether immunity to E6 and E7 evolves during chemoradiotherapy or affects survival. Using T cells from 2 HPV16+ patients, we conducted functional T-cell assays to identify candidate HPV-specific T cells and common T-cell receptor motifs, which we then analyzed across 86 patients with HPV-related cancers. The HPV-specific clones and E7-related T-cell receptor motifs expanded in the tumor microenvironment over the course of treatment, whereas non-HPV-specific T cells did not. In HPV16+ patients, improved recurrence-free survival was associated with HPV-responsive T-cell expansion during chemoradiotherapy.","prettyUrl":"colbert-2022-cir","following":false,"created":"01/14/2022","featured":false,"publishedDate":"01/14/2022","urlOrId":"colbert-2022-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a18e97e1-a48c-40ad-a350-5bffc127b25b","title":"Sensory nerves in melanoma impede the formation of tertiary lymphoid structures and anti-tumor immune responses","investigator":"Bunimovich, Yuri L.","investigatorInstitution":"Department of Dermatology, University of Pittsburgh","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"234":"kruglov-2022-melanoma"},"prettyUrlList":["kruglov-2022-melanoma"],"summary":"Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective anti-tumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered maturation of intratumoral high endothelial venules (HEVs) and limited formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent anti-tumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective anti-tumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting.","prettyUrl":"kruglov-2022-melanoma","following":false,"created":"01/06/2022","featured":false,"publishedDate":"01/06/2022","urlOrId":"kruglov-2022-melanoma","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fdefd2d8-d001-4b30-85eb-82db9f89e7d4","title":"Multi-objective Optimization Reveals Time- and Dose-Dependent Inflammatory Cytokine-Mediated Regulation of Human Stem Cell Derived T-cell Development","investigator":"Edgar, John","investigatorInstitution":"University of British Columbia, School of Biomedical Engineering","publicationName":"NPJ Regenerative Medicine","researchArea":"Other","prettyUrls":{"233":"edgar-2021-npjrm"},"prettyUrlList":["edgar-2021-npjrm"],"summary":"The generation of T-cells from stem cells in vitro could provide an alternative source of cells for immunotherapies. T-cell development from hematopoietic stem and progenitor cells (HSPCs) is tightly regulated through Notch pathway activation by Delta-like (DL) ligands 1 and 4. Other molecules, such as stem cell factor (SCF) and interleukin (IL)-7, play a supportive role in regulating the survival, differentiation, and proliferation of developing T-cells. Numerous other signaling molecules influence T-lineage development in vivo, but little work has been done to understand and optimize their use for T-cell production. Using a defined engineered thymic niche system, we undertook a multi-stage statistical learning-based optimization campaign and identified IL-3 and tumor necrosis factor α (TNFα) as a stage- and dose-specific enhancers of cell proliferation and T-lineage differentiation. We used this information to construct an efficient three-stage process for generating conventional TCRαβ+CD8+ T-cells expressing a diverse TCR repertoire from blood stem cells. Our work provides new insight into T-cell development and a robust system for generating T-cells to enable clinical therapies for treating cancer and immune disorders.","prettyUrl":"edgar-2021-npjrm","following":false,"created":"11/05/2021","featured":false,"publishedDate":"01/05/2022","urlOrId":"edgar-2021-npjrm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1f95c069-5f08-40e2-9a5f-4adad63af53b","title":"Epstein-Barr Virus+ B Cells in Breast Cancer Immune Response: A Case Report","investigator":"Aran, Andrea","investigatorInstitution":"Immunology Unit, Institut de Biotecnologia i Biomedicina, and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona","publicationName":"Frontiers in Immunology","researchArea":"Cancer","prettyUrls":{"231":"aran-2021-fi"},"prettyUrlList":["aran-2021-fi"],"summary":"EBV-specific T cells have been recently described to be involved in fatal encephalitis and myocarditis in cancer patients after immune checkpoint therapies. Here, we report the study of a human triple-negative breast cancer tumor (TNBC) and EBV-transformed B cells obtained from a patient-derived xenograft (PDX) that progressed into a lymphocytic neoplasm named xenograft-associated B-cell lymphoma (XABCL). T-cell receptor (TCR) high-throughput sequencing was performed to monitor the T-cell clonotypes present in the different samples. Forty-three T-cell clonotypes were found infiltrating the XABCL tissue after three passes in mice along 6 months. Eighteen of these (42%) were also found in the TNBC biopsy. TCR infiltrating the XABCL tissue showed a very restricted T-cell repertoire as compared with the biopsy-infiltrating T cells. Consequently, T cells derived from the TNBC biopsy were expanded in the presence of the B-cell line obtained from the XABCL (XABCL-LCL), after which the TCR repertoire obtained was again very restricted, i.e., only certain clonotypes were selected by the B cells. A number of these TCRs had previously been reported as sequences involved in infection, cancer, and/or autoimmunity. We then analyzed the immunopeptidome from the XABCL-LCL, to identify putative B-cell-associated peptides that might have been expanding these T cells. The HLA class I and class II-associated peptides from XABCL-LCL were then compared with published repertoires from LCL of different HLA typing. Proteins from the antigen processing and presentation pathway remained significantly enriched in the XABCL-LCL repertoire. Interestingly, some class II-presented peptides were derived from cancer-related proteins. These results suggest that bystander tumor-infiltrating EBV+ B cells acting as APC may be able to interact with tumor-infiltrating T cells and influence the TCR repertoire in the tumor site.","prettyUrl":"aran-2021-fi","following":false,"created":"10/18/2021","featured":false,"publishedDate":"11/04/2021","urlOrId":"aran-2021-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f8c69c15-19d2-46b2-99f2-951d276cd78b","title":"Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma","investigator":"Liu, Sixue","investigatorInstitution":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles","publicationName":"Cell Reports Medicine","researchArea":"Cancer Immunotherapy","prettyUrls":{"217":"liu-2021-crm"},"prettyUrlList":["liu-2021-crm"],"summary":"Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.","prettyUrl":"liu-2021-crm","following":false,"created":"08/19/2021","featured":false,"publishedDate":"11/02/2021","urlOrId":"liu-2021-crm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5d98be71-6c39-4c8b-9e64-bf82d2edd9c7","title":"The Similarity of Class II HLA Genotypes Defines Patterns of Autoreactivity in Idiopathic Bone Marrow Failure Disorders","investigator":"Simona Pagliuca","investigatorInstitution":"Translational Hematology and Oncology Research Department, Cleveland Clinic","publicationName":"Blood","researchArea":"Autoimmune Disorders","prettyUrls":{"230":"pagliuca-2021-b"},"prettyUrlList":["pagliuca-2021-b"],"summary":"Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T cell response to unknown antigens. As for other autoimmune disorders, the predilection for certain HLA profiles seems to represent an etiologic factor, however, the structure-function patterns involved in the self-presentation in this disease remain unclear.  Herein we analyzed the molecular landscape of HLA complexes of a cohort of 300 IAA patients and almost 3000 healthy and disease controls, by deeply dissecting their genotypic configurations, functional divergence, self-antigen binding capabilities and T cell receptor (TCR) repertoire specificities. Specifically, analysis of the evolutionary divergence of HLA genotypes (HED) showed that IAA patients carried class II HLA molecules whose antigen binding sites were characterized by a high level of structural homology, only partially explained by specific risk allele profiles. This pattern implies reduced HLA binding capabilities, confirmed by binding analysis of hematopoietic stem cell derived self-peptides. IAA phenotype was associated with the enrichment in a few amino acids at specific positions within the peptide-binding groove of DRB1 molecules, affecting the interface HLA-antigen-TCR β and potentially constituting the basis of T-cell dysfunction and autoreactivity. When analyzing associations with clinical outcomes, low HED was associated with risk of malignant progression and worse survival, underlying reduced tumor surveillance in clearing potential neoantigens derived from mechanisms of clonal hematopoiesis. Our data shed light on the immunogenetic risk associated with IAA etiology and clonal evolution, and on general pathophysiological mechanisms potentially involved also in other autoimmune disorders.","prettyUrl":"pagliuca-2021-b","following":false,"created":"10/29/2021","featured":false,"publishedDate":"10/29/2021","urlOrId":"pagliuca-2021-b","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"267e0152-3e1e-4f28-becd-ac2b83a31d19","title":"A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients With Locally Advanced or Metastatic Cancers","investigator":"Diab, Adi","investigatorInstitution":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"229":"diab-2021-ccr"},"prettyUrlList":["diab-2021-ccr"],"summary":"Purpose: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a co-stimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40.\n\nExperimental design: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01-10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity, and biomarker analyses.\n\nResults: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade {less than or equal to}2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at {greater than or equal to}0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies.\n\nConclusions: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary anti-tumor activity, and may serve as a partner for combination studies.\nExperimental Design: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01–10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity, and biomarker analyses.\n\nResults: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade ≤2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at ≥0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies.\n\nConclusions: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary anti-tumor activity, and may serve as a partner for combination studies.","prettyUrl":"diab-2021-ccr","following":false,"created":"08/04/2021","featured":false,"publishedDate":"10/25/2021","urlOrId":"diab-2021-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7d50ad87-88f0-4f00-b884-764c8d38ac10","title":"Positive and negative selection shape the human naïve B cell repertoire","investigator":"Meffre, Eric","investigatorInstitution":"Department of Immunobiology, Yale University","publicationName":"Journal of Clinical Investigation","researchArea":"Basic Immunology","prettyUrls":{"228":"chen-2021-jci"},"prettyUrlList":["chen-2021-jci"],"summary":"Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.","prettyUrl":"chen-2021-jci","following":false,"created":"10/25/2021","featured":false,"publishedDate":"10/25/2021","urlOrId":"chen-2021-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5b364172-4316-4508-9d28-fcb3cd15e552","title":"Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small cell lung cancer","investigator":"Federico, Lorenzo","investigatorInstitution":"Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center","publicationName":"Annals of Oncology","researchArea":"TIL","prettyUrls":{"227":"federico-2021-ao"},"prettyUrlList":["federico-2021-ao"],"summary":"Background: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small cell lung cancer (NSCLC) has not been well established. \n\nPatients and Methods: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, TCR sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. \n\nResults: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing CD103, PD-1, TIM3, and ICOS. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B cell infiltrates and tertiary lymphoid structures. While increased B cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. \n\nConclusions: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.","prettyUrl":"federico-2021-ao","following":false,"created":"08/23/2021","featured":false,"publishedDate":"10/15/2021","urlOrId":"federico-2021-ao","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c1b97d54-c413-4565-8885-65f75dec11c8","title":"Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer","investigator":"Chen, Ming","investigatorInstitution":"Zhejiang Cancer Hospital","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"226":"chen-2021-nc"},"prettyUrlList":["chen-2021-nc"],"summary":"Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.","prettyUrl":"chen-2021-nc","following":false,"created":"10/08/2021","featured":false,"publishedDate":"10/09/2021","urlOrId":"chen-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d89ae3c0-685e-4051-b42f-02047df8ac08","title":"CD200 Blockade Modulates Tumor Immune Microenvironment but Fails to Show Efficacy in Inhibiting Tumor Growth in a Murine Model of Melanoma","investigator":"Talebian, Fatemeh","investigatorInstitution":"Department of Pathology, College of Medicine, The Ohio State University","publicationName":"Frontiers in Cell and Developmental Biology","researchArea":"Cancer","prettyUrls":{"221":"talebian-2021-fcdb"},"prettyUrlList":["talebian-2021-fcdb"],"summary":"CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200+ Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R-/- mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R-/- or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ+ and TNF-α+ T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R-/- tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R-/- mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution.","prettyUrl":"talebian-2021-fcdb","following":false,"created":"09/02/2021","featured":false,"publishedDate":"09/20/2021","urlOrId":"talebian-2021-fcdb","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2d1851db-cedd-4c68-9905-8ce5e406de02","title":"Proteogenomic Discovery of Neoantigens Facilitates Personalized Multi-antigen Targeted T cell Immunotherapy for Brain Tumors","investigator":"Rivero-Hinojosa, Samuel","investigatorInstitution":"Center for Cancer and Immunology Research, Children’s National Research Institute","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"224":"rivero-hinojosa-2021-nc"},"prettyUrlList":["rivero-hinojosa-2021-nc"],"summary":"Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. We develop a low-input proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that novel splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting novel tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.","prettyUrl":"rivero-hinojosa-2021-nc","following":false,"created":"09/17/2021","featured":false,"publishedDate":"09/20/2021","urlOrId":"rivero-hinojosa-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1be67a99-528c-47fe-9fc9-30c58b9da621","title":"The AZD1222 COVID-19 vaccine induces a polyfunctional spike protein-specific Th1 response with a diverse TCR repertoire in humans","investigator":"Swanson II, Phillip A","investigatorInstitution":"Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health","publicationName":"Science Translational Medicine","researchArea":"Other","prettyUrls":{"223":"swanson-2021-stm"},"prettyUrlList":["swanson-2021-stm"],"summary":"AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 296 unique vaccine recipients aged 18 to 85 years who enrolled in the phase 2/3 COV002 trial. Total spike protein-specific CD4+ T cell helper type 1 (Th1) and CD8+ T cell responses were increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T cell receptor (TCR) β sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for both AZD1222-induced CD4+ and CD8+ T cell responses. Overall, AZD1222 vaccination induced a polyfunctional Th1-dominated T cell response, with broad CD4+ and CD8+ T cell coverage across the SARS-CoV-2 spike protein.","prettyUrl":"swanson-2021-stm","following":false,"created":"08/16/2021","featured":false,"publishedDate":"09/14/2021","urlOrId":"swanson-2021-stm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ec0fe735-586e-48ab-b646-9bcfbf44f139","title":"SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation","investigator":"Delmonte, Ottavia M.","investigatorInstitution":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy of Infectious Diseases, National Institutes of Health","publicationName":"Blood","researchArea":"Immunocompetence","prettyUrls":{"222":"delmonte-2021-b"},"prettyUrlList":["delmonte-2021-b"],"summary":"SAM and SH3 domain-containing 3 (SASH3), also called SH3-containing Lymphocyte Protein (SLY1) is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias. Patients exhibited CD4+ T cell lymphopenia, decreased T cell proliferation and cell cycle progression, and increased T cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor alpha (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B and NK cell lymphopenia. Lentivirus-mediated transfer of the SASH3 cDNA corrected protein expression, in vitro proliferation and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in Sly1-/- and Sly1D/Dmutant mice, highlighting an important role of SASH3 in human lymphocyte function and survival.","prettyUrl":"delmonte-2021-b","following":false,"created":"09/03/2021","featured":false,"publishedDate":"09/07/2021","urlOrId":"delmonte-2021-b","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3028f52c-81cb-49dd-a146-4adf4389118d","title":"Next-Generation Sequencing-Based Monitoring of Circulating Tumor DNA Reveals Clonotypic Heterogeneity in Untreated PTCL","investigator":"Miljkovic, Milos D.","investigatorInstitution":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health","publicationName":"Blood Advances","researchArea":"Cancer","prettyUrls":{"220":"miljkovic-2021-ba"},"prettyUrlList":["miljkovic-2021-ba"],"summary":"Peripheral T-cell lymphomas (PTCL) have marked biologic and clinical heterogeneity, which confounds treatment decisions. Advances in circulating tumor DNA (ctDNA) assays employing next generation sequencing (NGS) has improved the detection of molecular relapse and driver mutations in diffuse large B-cell lymphoma, and highlight the potential utility of ctDNA across lymphomas. We investigated NGS-based monitoring of T-cell receptor (TCR) sequences in PTCL patients undergoing frontline treatment (NCT00001337). Of 45 patients, 34 (76%) had tumor-specific clonotypes of the TCR β or ɣ genes identified, which included 18 (86%) from baseline tissue and 16 (67%) from baseline serum. Twenty-five (74%) patients had both TCRβ and TCRɣ clonotypes, 23 (68%) patients had more than one TCRɣ clonotype, and 4 (9%) had multiple TCRβ or TCRɣ clonotypes, demonstrating significant intra-patient clonotypic heterogeneity. Among 24 patients with available serial serum samples during treatment, 9 (38%) cleared ctDNA after 2 cycles of therapy, and 11 (46%) patients had detectable ctDNA at the end of treatment. Patients with detectable ctDNA after therapy showed a trend towards worse survival. Notably, two patients with persistently detectable ctDNA after therapy remain in remission with 10-years of follow-up. Clonotypic heterogeneity in tumors and persistence despite long-term remission suggests variability in oncological potential.","prettyUrl":"miljkovic-2021-ba","following":false,"created":"09/01/2021","featured":false,"publishedDate":"09/02/2021","urlOrId":"miljkovic-2021-ba","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bb683b7f-4f1f-4816-bfea-12e5b293e61f","title":"Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy","investigator":"Casanova, Jean-Laurent","investigatorInstitution":"The Rockefeller University","publicationName":"Cell","researchArea":"Dermatology","prettyUrls":{"219":"beziat-2021-cell"},"prettyUrlList":["beziat-2021-cell"],"summary":"We study a patient with the human papilloma virus (HPV)-2-driven \"tree-man\" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.","prettyUrl":"beziat-2021-cell","following":false,"created":"09/01/2021","featured":false,"publishedDate":"09/02/2021","urlOrId":"beziat-2021-cell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d1668756-c766-4721-a1db-a402dfccbe1b","title":"HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related autoinflammatory disease","investigator":"Poli, Cecilia","investigatorInstitution":"Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo","publicationName":"Blood","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"218":"martinez-2021-b"},"prettyUrlList":["martinez-2021-b"],"summary":"Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe auto-inflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and auto- inflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.","prettyUrl":"martinez-2021-b","following":false,"created":"09/01/2021","featured":false,"publishedDate":"09/02/2021","urlOrId":"martinez-2021-b","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7bfb9e61-86b3-4569-87e4-0e6c04e04843","title":"Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response","investigator":"Kvistborg, Pia","investigatorInstitution":"Netherlands Cancer Institute, Department of Molecular Oncology & Immunology","publicationName":"PNAS","researchArea":"Cancer Immunotherapy","prettyUrls":{"212":"gangaev-2021-pnas"},"prettyUrlList":["gangaev-2021-pnas"],"summary":"Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action ofPD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 Tcell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the circulating melanoma-reactiveCD8 T cell response was unaltered upon PD-1 blockade. In contrast, a broadening of the circulating melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade have distinct mechanisms of action. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.","prettyUrl":"gangaev-2021-pnas","following":false,"created":"07/16/2021","featured":false,"publishedDate":"08/20/2021","urlOrId":"gangaev-2021-pnas","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2aecf67b-8f36-4389-85d2-2fb8b7e66d44","title":"Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial","investigator":"Scott J. Antonia","investigatorInstitution":"Duke Cancer Institute, Duke University School of Medicine","publicationName":"Nature Medicine","researchArea":"TIL","prettyUrls":{"216":"creelan-2021-nm"},"prettyUrlList":["creelan-2021-nm"],"summary":"Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion and interleukin-2, followed by maintenance nivolumab. The end point of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval, 3-29%). Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer.","prettyUrl":"creelan-2021-nm","following":false,"created":"08/17/2021","featured":false,"publishedDate":"08/19/2021","urlOrId":"creelan-2021-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"be54b338-f570-4477-afde-0756d9d3d27f","title":"The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination","investigator":"Beilinison, Helen A","investigatorInstitution":"Department of Immunobiology, Yale School of Medicine, Yale University","publicationName":"Journal of Experimental Medicine","researchArea":"Basic Immunology","prettyUrls":{"215":"beilinson-2021-jem"},"prettyUrlList":["beilinson-2021-jem"],"summary":"Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1-383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo are poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (d215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency including an increased Igk+:Igl+ B cell ratio and decreased recombination of Igh, Igk, Igl, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1d215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways including control of the balance between short- and long-range recombination.","prettyUrl":"beilinson-2021-jem","following":false,"created":"08/02/2021","featured":false,"publishedDate":"08/09/2021","urlOrId":"beilinson-2021-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"322a46d5-7ed3-4749-9799-f0df1fe6d0a8","title":"Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans","investigator":"Barouch, Dan H.","investigatorInstitution":"Harvard Medical School","publicationName":"Nature","researchArea":"Vaccine efficacy","prettyUrls":{"214":"alter-2021-n"},"prettyUrlList":["alter-2021-n"],"summary":"The Ad26.COV2.S vaccine1-3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I-IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.","prettyUrl":"alter-2021-n","following":false,"created":"07/27/2021","featured":false,"publishedDate":"07/28/2021","urlOrId":"alter-2021-n","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9a376328-dfea-4679-8fb7-13e49580e4ff","title":"Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance","investigator":"Smith, Kellie N","investigatorInstitution":"Department of Oncology, Johns Hopkins University School of Medicine","publicationName":"Journal for ImmunoTherapy of Cancer","researchArea":"Cancer","prettyUrls":{"213":"cottrell-2021-jitc"},"prettyUrlList":["cottrell-2021-jitc"],"summary":"T-cell receptor sequencing (TCRseq) enables tracking of T-cell clonotypes recognizing the same antigen over time and across biological compartments. TCRseq has been used to test if cross-reactive antitumor T cells are responsible for development of immune-related adverse events (irAEs) following immune checkpoint blockade. Prior studies have interpreted T-cell clones shared among the tumor and irAE as evidence supporting this, but interpretations of these findings are challenging, given the constraints of TCRseq. Here we capitalize on a rare opportunity to understand the impact of potential confounders, such as sample size, tissue compartment, and collection batch/timepoint, on the relative proportion of shared T-cell clones between an irAE and tumor specimens. TCRseq was performed on tumor-involved and -uninvolved tissues, including an irAE, that were obtained throughout disease progression and at the time of rapid autopsy from a patient with renal cell carcinoma treated with programmed death-1 (PD-1) blockade. Our analyses show significant effects of these confounders on our ability to understand T-cell receptor overlap, and we present mitigation strategies and study design recommendations to reduce these errors. Implementation of these strategies will enable more rigorous TCRseq-based studies of immune responses in human tissues, particularly as they relate to antitumor T-cell cross-reactivity in irAEs following checkpoint blockade.","prettyUrl":"cottrell-2021-jitc","following":false,"created":"07/20/2021","featured":false,"publishedDate":"07/21/2021","urlOrId":"cottrell-2021-jitc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"932112f9-dee2-4013-abb1-24d67aa3d74c","title":"Intrathecal activation of CD8+ memory T cells in IgG4-related disease of the brain parenchyma","investigator":"Friedrich, Mirco","investigatorInstitution":"German Cancer Research Center (DKFZ)","publicationName":"EMBO Molecular Medicine","researchArea":"Autoimmune Disorders","prettyUrls":{"211":"friedrich-2021-embomm"},"prettyUrlList":["friedrich-2021-embomm"],"summary":"IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and patho- physiological mechanisms of IgG4-RD remain elusive. There are very few cases of IgG4-RD with isolated central nervous system manifes- tation. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4- RD. Our data illustrate an IgG4-RD-associated polyclonal T-cell response in the CSF and an oligoclonal T-cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8+ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)-CD74 signaling to immature B cells and CC-chemokine ligand 5 (CCL5)-mediated recruitment of cytotoxic CD4+ T cells. These findings highlight the central role of T cells in sustaining IgG4-RD and open novel avenues for targeted therapies.","prettyUrl":"friedrich-2021-embomm","following":false,"created":"05/04/2021","featured":false,"publishedDate":"07/07/2021","urlOrId":"friedrich-2021-embomm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"63b3fa7e-71ca-4260-8621-03d2cabc87d5","title":"Intrathymic differentiation of natural antibody-producing plasma cells in human neonates","investigator":"Cordero, Hector","investigatorInstitution":"Columbia University Medical Center","publicationName":"Nature Communications","researchArea":"Innate Immunity","prettyUrls":{"210":"cordero-2021-nc"},"prettyUrlList":["cordero-2021-nc"],"summary":"The thymus is a central lymphoid organ responsible for the development of T cells. Here, we show that the thymus of human neonates also contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells (ASC) are comprised within a larger subset of B cells lacking expression of the complement receptors CD21 and CD35 and sharing the expression of signature genes defining mouse B1 cells. Single-cell transcriptomic, clonal correspondence and in vitro differentiation assays supported the intrathymic differentiation of CD138+ plasma cells alongside other B cell subsets with distinctive molecular phenotypes. Neonatal thymic plasma cells also included clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.","prettyUrl":"cordero-2021-nc","following":false,"created":"06/22/2021","featured":false,"publishedDate":"06/28/2021","urlOrId":"cordero-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f8dace30-0086-4b22-b1a7-6aeebdf24ede","title":"Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation","investigator":"Simona Pagliuca","investigatorInstitution":"Translational Hematology and Oncology Research Program, Department of Hematology and Oncology, Cleveland Clinic Foundation","publicationName":"JCI insight","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"209":"pagliuca-2021-jcii"},"prettyUrlList":["pagliuca-2021-jcii"],"summary":"An effective T-cell receptor (TCR) repertoire diversification contributes to the success of hematopoietic cell transplantation (HCT). A full understanding of the patterns of T cell adaptive reconstitution may help in the discrimination of alloreactive responses. Herein, we prospectively studied the superstructure of TCR repertoire in 135 serial specimens from 35 patients receiving HCT for myeloid malignancies. \nPaired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were the hallmarks of the T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3–based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post–\nallo-HCT phase, while autoreactive clones were more expanded in case of graft-versus-host disease occurrence. These findings shed light on post–allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.\n\n\n\nKeywords: TCR, adaptive immune competence, HCT, GVHD, clonal expansion\n\nKey points: \n\n•\tNGS deep TCR VβCDR3 sequencing allows for assessing clonal T-cell repertoire T-cell dynamics and tracing individual clonal specificities following hematopoietic stem cell transplantation.\n•\tAfter allogeneic hematopoietic cell transplantation, the restoration of TCR recognition spectrum is protracted and shaped by the post-transplant clinical course, diverging from the donor repertoire.   \n•\tTCR VβCDR3 can serve as a quantifiable marker of specific immune responses defining a unique structure minimally overlapping with donor repertoire.","prettyUrl":"pagliuca-2021-jcii","following":false,"created":"06/24/2021","featured":false,"publishedDate":"06/28/2021","urlOrId":"pagliuca-2021-jcii","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e146af14-2545-42e9-9a07-acf35b3521dc","title":"Low neoantigen expression and poor T cell priming underlie early immune escape in colorectal cancer","investigator":"Westcott, Peter MK","investigatorInstitution":"David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology","publicationName":"Nature Cancer","researchArea":"Cancer","prettyUrls":{"208":"westcott-2021-nc"},"prettyUrlList":["westcott-2021-nc"],"summary":"Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB) (e.g., those with microsatellite instability (MSI)). Whether low TMB cancers, which are largely refractory to immunotherapy, harbor potentially immunogenic neoantigens remains unclear. Here, we show that tumors from all patients with microsatellite stable (MSS) colorectal cancer (CRC) express clonal predicted neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels compared to those in MSI CRC. Using a versatile platform for modulating neoantigen expression in CRC organoids and transplantation into the distal colon of mice, we show that low expression precludes productive cross priming and drives immediate T cell dysfunction. Strikingly, experimental or therapeutic rescue of priming rendered T cells capable of controlling tumors with low neoantigen expression. These findings underscore a critical role of neoantigen expression level in immune evasion and therapy response.","prettyUrl":"westcott-2021-nc","following":false,"created":"06/21/2021","featured":false,"publishedDate":"06/22/2021","urlOrId":"westcott-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"dcecacac-f025-4057-894a-63e54a367790","title":"Expansion of Unique Hepatitis C Virus Specific Public CD8+ T Cell Clonotypes during Acute Infection and Reinfection","investigator":"Shoukry, Naglaa H","investigatorInstitution":"Département de médecine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal","publicationName":"Journal of Immunology","researchArea":"Infectious Disease","prettyUrls":{"207":"mazouz-2021-ji"},"prettyUrlList":["mazouz-2021-ji"],"summary":"Hepatitis C virus (HCV) infection resolves spontaneously in approximately 25% of acutely infected humans where viral clearance is mediated primarily by virus specific CD8+ T cells. Previous cross-sectional analysis of the CD8+ T cell receptor (TCR) repertoire targeting two immunodominant HCV epitopes reported widespread use of public TCRs shared by different subjects, irrespective of infection outcome. However, little is known about the evolution of the public TCR repertoire during acute HCV and whether cross- reactivity to other antigens can influence infectious outcome. Here, we analyzed the CD8+ TCR repertoire specific to the immunodominant and cross-reactive HLA-A2 restricted NS3-1073 epitope during acute HCV in humans progressing to either spontaneous resolution or chronic infection, and at ~1-year following viral clearance. TCR repertoire diversity was comparable among all groups with preferential usage of the V04 and V06 gene families. We identified a set of thirteen public clonotypes in HCV-infected humans independent of infection outcome. Six public clonotypes used the V04 gene family. Several public clonotypes were long-lived in resolvers and expanded upon reinfection. By mining publicly available data, we identified several low frequency CDR3 sequences in the HCV-specific repertoire matching human TCRs specific for other HLA-A2 restricted epitopes from melanoma, cytomegalovirus, influenza A, Epstein-Barr and yellow fever viruses but they were of low frequency and limited cross-reactivity. In conclusion, we identified thirteen new public human CD8+ TCR clonotypes unique to HCV that expanded during acute infection and reinfection. The low frequency of cross- reactive TCRs suggest that they are not major determinants of infectious outcome.","prettyUrl":"mazouz-2021-ji","following":false,"created":"06/11/2021","featured":false,"publishedDate":"06/21/2021","urlOrId":"mazouz-2021-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c598d17c-127f-4b3d-8a4e-47860f8b00c8","title":"IL-32 supports the survival of malignant T cells in cutaneous T cell lymphoma","investigator":"Clark, Rachael A.","investigatorInstitution":"Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School","publicationName":"Journal of Investigative Dermatology","researchArea":"Dermatology","prettyUrls":{"206":"yu-2021-jid"},"prettyUrlList":["yu-2021-jid"],"summary":"Cutaneous T-cell lymphoma (CTCL) is a heterogeneous collection of non-Hodgkin’s lymphomas derived from T cells that are tropic for the skin. Our understanding of this disease has been hampered by the fact that malignant T cells survive poorly in culture and do not survive well even in sophisticated xenograft models ( Townsend et al., 2016 ). Isolation and culture of T cells from CTCL skin lesions lead to an overgrowth of benign infiltrating T cells and loss of the malignant T-cell clone. It is an inescapable irony that malignant T cells capable of killing patients die in even the most supportive in vitro and in vivo environments. These cells appear to require a survival factor found in the skin but not replicated by in vitro and in vivo murine systems.","prettyUrl":"yu-2021-jid","following":false,"created":"06/03/2021","featured":false,"publishedDate":"06/03/2021","urlOrId":"yu-2021-jid","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"08e34f68-0817-4493-a12f-088cb3aa6b88","title":"Transcriptional programs of neoantigen- specific TIL in anti-PD-1-treated lung cancers","investigator":"Smith, Kellie","investigatorInstitution":"Johns Hopkins Unversity","publicationName":"Nature","researchArea":"Cancer","prettyUrls":{"205":"caushi-2021-n"},"prettyUrlList":["caushi-2021-n"],"summary":"PD-1 blockade unleashes CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunctionprograms in tumour-infltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We found both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TILs express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signaling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.","prettyUrl":"caushi-2021-n","following":false,"created":"04/19/2021","featured":false,"publishedDate":"06/02/2021","urlOrId":"caushi-2021-n","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7b39cc48-f684-4c97-8a08-aa5386cebb27","title":"Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire","investigator":"Reinhardt, Richard Lee","investigatorInstitution":"National Jewish Health","publicationName":"PLoS Pathogens","researchArea":"Infectious Disease","prettyUrls":{"204":"brown-20201-pp"},"prettyUrlList":["brown-20201-pp"],"summary":"The CD4+ T cell response is critical to host protection against helminth infection. How this response varies across different hosts and tissues remains an important gap in our understanding. Using IL-4-reporter mice to identify responding CD4+ T cells to Nippostrongylus brasiliensis infection, T cell receptor sequencing paired with novel clustering algorithms revealed a broadly reactive and clonally diverse CD4+ T cell response. While the most prevalent clones and clonotypes exhibited some tissue selectivity, most were observed to reside in both the lung and lung-draining lymph nodes. Antigen-reactivity of the broader repertoires was predicted to be shared across both tissues and individual mice. Transcriptome, trajectory, and chromatin accessibility analysis of lung and lymph-node repertoires revealed three unique but related populations of responding IL-4+ CD4+ T cells consistent with T follicular helper, T helper 2, and a transitional population sharing similarity with both populations. The shared antigen reactivity of lymph node and lung repertoires combined with the adoption of tissue-specific gene programs allows for the pairing of cellular and humoral responses critical to the orchestration of anti-helminth immunity.","prettyUrl":"brown-20201-pp","following":false,"created":"02/10/2021","featured":false,"publishedDate":"05/18/2021","urlOrId":"brown-20201-pp","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5609bfe7-453d-4777-8a2d-515c45ce6756","title":"Clonal analysis of immunodominance and cross-reactivity of the CD4 T cell response to SARS-CoV-2","investigator":"Cassotta, Antonino","investigatorInstitution":"Institute for Research in Biomedicine","publicationName":"Science","researchArea":"Infectious Disease","prettyUrls":{"203":"low-2021-s"},"prettyUrlList":["low-2021-s"],"summary":"The identification of CD4+ T cell epitopes is instrumental for the design of subunit vaccines for broad protection against coronaviruses. Here we demonstrate in COVID-19-recovered individuals a robust CD4+ T cell response to naturally processed SARS-CoV-2 spike (S) and nucleoprotein (N), including effector, helper, and memory T cells. By characterizing 2943 S-reactive T cell clones from 34 individuals, we found that RBD is highly immunogenic, and that 33% of RBD-reactive clones and 94% of individuals recognized a conserved immunodominant S346-365 region comprising nested HLA-DR- and HLA-DP-restricted epitopes. Using pre- and post-COVID-19 samples and S proteins from endemic coronaviruses, we identify cross-reactive T cells targeting multiple S protein sites. The immunodominant and cross-reactive epitopes identified can inform vaccination strategies to counteract emerging SARS-CoV-2 variants.","prettyUrl":"low-2021-s","following":false,"created":"04/14/2021","featured":false,"publishedDate":"05/14/2021","urlOrId":"low-2021-s","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e74ca34e-3767-4e93-8060-a4711a0adb9c","title":"Distinct populations of antigen specific tissue resident CD8 T cells in human cervix mucosa","investigator":"Tao Peng","investigatorInstitution":"University of Washington","publicationName":"JCI Insight","researchArea":"Other","prettyUrls":{"202":"peng-2021-jcii"},"prettyUrlList":["peng-2021-jcii"],"summary":"The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STI). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue resident memory T cells (TRM) in human FRT is lacking. We have taken single-cell RNA sequencing approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There are significantly more CD8 than CD4 T cells. Unsupervised clustering and trajectory analysis identify distinct populations of CD8 T cells with IFNGhiGZMBlowCD69hiCD103low or IFNGlowGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescent staining shows that CD103+ CD8 TRM cells preferentially localize in epithelium while CD69+ CD8 TRM distribute evenly in epithelium and stroma. Ex vivo assays indicate up to 14% of cervical CD8 TRM clonotypes are HSV-2 reactive in HSV-2-seropositive persons, reflecting physiologically relevant localization. Our studies identify subgroups of CD8 TRM in the human ectocervix that exhibit distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRM is an important approach for improving host defenses to STI.","prettyUrl":"peng-2021-jcii","following":false,"created":"05/10/2021","featured":false,"publishedDate":"05/10/2021","urlOrId":"peng-2021-jcii","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1e3ed1e4-b333-4989-9fab-fb9554cdd30e","title":"Functional characterization of CD4+ T-cell receptors cross-reactive for SARS-CoV-2 and endemic coronaviruses","investigator":"Smith, Kellie","investigatorInstitution":"Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Medicine","publicationName":"Journal of Clinical Investigation","researchArea":"Infectious Disease","prettyUrls":{"200":"dykema-2021-jci"},"prettyUrlList":["dykema-2021-jci"],"summary":"Background: Recent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to cross-recognition by T-cells specific for common cold coronaviruses (CCCs). True T-cell cross-reactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.\n\nMethods: We used the ViraFEST platform to identify T cell responses cross-reactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC cross-reactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.\n\nResults: Memory CD4+ T-cell clonotypes that cross-recognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Cross-reactive T-cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to mono-specific CD4+ T-cells, which was consistent with lower functional avidity of their TCRs for SARS CoV-2 relative to CCC.\n\nConclusions: For the first time, our data confirm the existence of unique memory CD4+ T cell clonotypes cross-recognizing SARS-CoV-2 and CCCs. The lower avidity of cross-reactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that pre-existing CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these cross-reactive T-cell responses impact clinical outcomes in COVID-19 patients.","prettyUrl":"dykema-2021-jci","following":false,"created":"04/21/2021","featured":false,"publishedDate":"04/22/2021","urlOrId":"dykema-2021-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6642558a-918a-490e-bb39-78c12fe3a733","title":"Select antitumor cytotoxic CD8+ T clonotypes expand in patients with chronic lymphocytic leukemia treated with ibrutinib","investigator":"Baptista, Maria Joao","investigatorInstitution":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health","publicationName":"Clinical Cancer Research","researchArea":"Response to Therapeutic Agent","prettyUrls":{"199":"baptista-2021-ccr"},"prettyUrlList":["baptista-2021-ccr"],"summary":"Purpose: In chronic lymphocytic leukemia (CLL), the T-cell receptor (TCR) repertoire is skewed and tumor-derived antigens are hypothesized as drivers of oligoclonal expansion. Ibrutinib, a standard treatment for CLL, inhibits not only Bruton tyrosine kinase of the B-cell receptor signaling pathway, but also interleukin-2-inducible kinase of the TCR signaling pathway. T-cell polarization and activation are affected by ibrutinib, but it is unknown if T cells contribute to clinical response.\n\nExperimental Design: High-throughput TCRß sequencing was performed in 77 longitudinal samples from 26 CLL patients treated with ibrutinib. TCRß usage in CD4+ and CD8+ T cells and granzyme B expression were assessed by flow cytometric analysis. Antitumor cytotoxicity of T cells expanded with autologous CLL cells or with antigen-independent anti-CD3/CD28/CD137 beads was tested.\n\nResults: The clonality of the TCR repertoire increased at the time of response. With extended treatment, TCR clonality remained stable in patients with sustained remission and decreased in patients with disease progression. Expanded clonotypes were rarely shared between patients, indicating specificity for private antigens. Flow cytometry demonstrated a predominance of CD8+ cells among expanded clonotypes. Importantly, bulk T cells from responding patients were cytotoxic against autologous CLL cells in vitro and selective depletion of major expanded clonotypes reduced CLL cell killing.\n\nConclusions: In patients with CLL, established T-cell responses directed against tumor are suppressed by disease and reactivated by ibrutinib.","prettyUrl":"baptista-2021-ccr","following":false,"created":"02/23/2021","featured":false,"publishedDate":"04/20/2021","urlOrId":"baptista-2021-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"127959a5-a7c9-4477-9f2e-06705f9f8ba0","title":"B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma","investigator":"Bruno, Tullia","investigatorInstitution":"University of Pittsburgh, Department of Immunology","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"198":"ruffin-2021-nc"},"prettyUrlList":["ruffin-2021-nc"],"summary":"Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome.  GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a (SEMA4A) expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.","prettyUrl":"ruffin-2021-nc","following":false,"created":"04/12/2021","featured":false,"publishedDate":"04/15/2021","urlOrId":"ruffin-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1d4f576f-39a9-44e7-8540-4c9bf457f51f","title":"Generation of self-reactive, shared T-cell receptor α chains in the human thymus","investigator":"Arstila, T.Petteri","investigatorInstitution":"Research Programs Unit, Translational Immunology, and Medicum, University of Helsinki","publicationName":"Journal of Autoimmunity","researchArea":"Basic Immunology","prettyUrls":{"197":"heikkila-2021-ja"},"prettyUrlList":["heikkila-2021-ja"],"summary":"T-cell receptors (TCRs) are heterodimers consisting of TCRa and TCRb chains that are generated in a semistochastic process of genetic recombination. The estimated total diversity exceeds 10^8 unique TCRs. We have analyzed TCR clonotypes at their early developmental stage in thymus showed earlier that a surprisingly high fraction of TCR clonotypes are shared between unrelated individuals, concerning particularly TCRa chains with abundant clone sizes. Here, we studied the generation of TCRs associated with antigens that are previously  identified in the context of type 1 diabetes (T1D) and HIV. We show that the human thymus prefers the generation of  T1D-associated TCRa chains over HIV-associated chains. Furthermore, analysis of circulating repertoires shows that these T1D-associated chains are not lost in the negative selection nor predominantly converted to regulatory T-cell lineage.","prettyUrl":"heikkila-2021-ja","following":false,"created":"04/07/2021","featured":false,"publishedDate":"04/07/2021","urlOrId":"heikkila-2021-ja","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"cd09abd3-5c8b-465f-ae98-bf3f810b3229","title":"Treatment-induced immune cell priming as a potential explanation for an outstanding anti-tumor response in a patient with metastatic colorectal cancer","investigator":"Duhen, Thomas","investigatorInstitution":"Earle A. Chiles Research Institute | Providence Cancer Institute","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"196":"rajamanickam-2021-cir"},"prettyUrlList":["rajamanickam-2021-cir"],"summary":"Microsatellite stable (MSS) colorectal cancers (CRC) are known to harbor low mutation burden, a limited immune cell infiltration and thereby respond poorly to immunotherapy. Here we report a case of metastatic CRC with an outstanding anti-cancer immune response. Briefly, the primary tumor was resected in 2012 and the patient received several cycles of chemotherapy until 2017. In 2018, he underwent a left hepatectomy to remove a new metastasis. Analysis of this tumor revealed a strong CD8 T cell immune response. A high frequency of CD8 T cells co-expressed CD39 and CD103, a phenotype characteristic of tumor-reactive cells. Using whole exome sequencing, we identified somatic mutations recognized by CD39+CD103+ CD8 T cells. The observed reactivity against the tumor was dominated by the response to a single mutation that emerged in the colorectal liver metastasis. Importantly, somatic mutations that were not immunogenic in the primary tumor led to robust CD8 T cell expansion later during disease progression. Our data suggest that the cytotoxic treatment regimen received by the patient might be responsible for this effect. Hence, the capacity of cytotoxic regimens to prime the immune system in CRC patients should be investigated further and might provide a rationale for combination with immunotherapy.","prettyUrl":"rajamanickam-2021-cir","following":false,"created":"04/02/2021","featured":false,"publishedDate":"04/05/2021","urlOrId":"rajamanickam-2021-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"062d2746-499b-4052-8799-5af771f655df","title":"Thymic atrophy creates holes in Treg-mediated immuno-regulation via impairment of an antigen-specific clone","investigator":"Su, Dong-Ming","investigatorInstitution":"Dept. of Microbiology, Immunology and Genetics, University of North Texas Health Science Center","publicationName":"Immunology","researchArea":"Basic Immunology","prettyUrls":{"195":"thomas-2021-immunology"},"prettyUrlList":["thomas-2021-immunology"],"summary":"Age-related thymic involution results in reduced output of naïve conventional T (Tcon) cells. However, its impact on regulatory T (Treg) cells is insufficiently understood. Given evidence that thymic Treg (tTreg) cell generation is enhanced in the aged, involuted thymus and that the aged periphery accumulates peripheral Treg (pTreg) cells, we asked why these Treg cells are unable to effectively attenuate increased auto-reactivity induced chronic inflammation in the elderly. We utilized a mock self-antigen chimeric mouse model, in which membrane-bound ovalbumin (mOVA) transgenic mice bearing a FoxN1-floxed gene for induction of conditional thymic involution, received MHC-II restricted, OVA-recognizing T cell receptor (TCR) transgenic progenitor cells. The chimeric mice with thymic involution exhibited a significant decrease in OVA-specific tTreg and pTreg cells, but not polyclonal (pan)-Treg cells. The OVA-specific pTreg cells were significantly less able to suppress OVA stimulation induced proliferation in vitro. Further, these cells exhibited intrinsic defects, displaying lower IL-2R expression coupled with lower FoxP3 expression upon OVA stimulation. Additionally, we conducted preliminary TCR repertoire diversity sequencing for Treg cells among recent thymic emigrants (RTEs) from RagGFP-FoxP3RFP dual reporter mice and observed a trend for decreased diversity in mice with thymic involution compared to littermates with normal thymus. In sum, these data indicate that although the effects of age-related thymic involution do not affect pan-Treg generation, a certain tissue-specific Treg clone is intrinsically impaired and not undergoing normal agonist selection, which could result in inability to attenuate age-related chronic inflammation.","prettyUrl":"thomas-2021-immunology","following":false,"created":"03/22/2021","featured":false,"publishedDate":"03/24/2021","urlOrId":"thomas-2021-immunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f8c5743d-ff44-47fc-88a7-0609e801eed6","title":"Complete Response to Programmed Cell Death-1 Blockade Following EBV-specific Adoptive T-cell Therapy in a Patient with Metastatic Nasopharyngeal Carcinoma","investigator":"Corey Smith","investigatorInstitution":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute","publicationName":"NJP Precision Oncology","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"194":"smith-2021-njppo"},"prettyUrlList":["smith-2021-njppo"],"summary":"Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated heterogeneous disease and is characterized by peri-tumoral immune infiltrate. Adoptive T-cell therapy (ACT) has emerged as a potential therapeutic strategy for NPC. However, the tumour microenvironment remains a major roadblock for successful implementation of ACT in clinical settings. Expression of checkpoint molecules by malignant cells can inhibit the effector function of adoptively transferred EBV-specific T cells. Here we present a novel case report of a patient with metastatic NPC who was successfully treated with a combination of EBV-specific ACT and programmed cell death-1 blockade therapy. Following combination immunotherapy, the patient showed complete resolution of metastatic disease with no evidence of disease relapse for 22 months. Follow up immunological analysis revealed dramatic restructuring of the global T-cell repertoire that was coincident with the clinical response. This case report provides an important platform for translating these findings to a larger cohort of NPC patients.","prettyUrl":"smith-2021-njppo","following":false,"created":"01/31/2021","featured":false,"publishedDate":"03/22/2021","urlOrId":"smith-2021-njppo","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7577484f-af76-4f3d-b651-7ca4cfa6159f","title":"Clonally focused public and private T cells in resected brain tissue from surgeries to treat children with intractable seizures.","investigator":"Owens, Geoffrey C.","investigatorInstitution":"Department of Neurosurgery, David Geffen School of Medicine at UCLA","publicationName":"Frontiers in Immunology","researchArea":"Other","prettyUrls":{"193":"chang-2021-fi"},"prettyUrlList":["chang-2021-fi"],"summary":"Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) V chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 clonotypes indicated that T cells in the brain were clonally restricted. The top 50 clonotypes comprised both public and private (patient specific) clonotypes, and the TCR V chain third complementarity region (CDR3) of the most abundant public clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clonotypes were CD8 effector T cells, indicating that they are likely to be pathologically relevant.","prettyUrl":"chang-2021-fi","following":false,"created":"03/16/2021","featured":false,"publishedDate":"03/17/2021","urlOrId":"chang-2021-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"95fadbc3-34c7-4475-85a6-b06fb0c58a48","title":"Response to Hypomethylating Agents in Myelodysplastic Syndrome Is Associated with Emergence of Novel TCR Clonotypes","investigator":"Abbas, Hussein A.","investigatorInstitution":"University of Texas MD Anderson Cancer Center","publicationName":"Frontiers in Immunology","researchArea":"Response to Therapeutic Agent","prettyUrls":{"192":"abbas-2021-fi"},"prettyUrlList":["abbas-2021-fi"],"summary":"Aberrant T-cell function is implicated in the pathogenesis of myelodysplastic syndrome (MDS).  Monitoring the T-cell receptor (TCR) repertoire can provide insights into T-cell adaptive immunity. Previous studies found skewed TCR repertoires in MDS compared to healthy patients, however these studies used mRNA-based spectratyping have limitations. Furthermore, evaluating the TCR repertoire in context of hypomethylating agents (HMAs) treatment can provide insights into the dynamics of T-cell mediated responses in MDS. We conducted immunosequencing of the CDR3 regions of TCRβ chains in bone marrows of 11 MDS patients prior (n=11) and following treatment (n=26) with hypomethylating agents, alongside bone marrows from 4 healthy donors as controls. TCR repertoires in MDS patients were more clonal and less diverse than healthy donors. However, unlike previous reports, we did not observe significant skewness in CDR3 length or spectratyping. The global metrics of TCR profiling including richness, clonality, overlaps were not significantly changed was observed in MDS patients following treatment with HMAs regardless of response. However, an emergence of novel clonotypes in MDS patients who responded to treatment, while non-responders had a higher frequency of contracted clonotypes following treatment. By applying GLIPH for antigen prediction, we found rare TCR specificity clusters shared by TCR clonotypes from different patients at pre- or following treatment. Our data show clear differences in TCR repertoires of MDS compared with healthy patients and that novel TCR clonotype emergence in response to HMA therapy was correlated with response. This suggests that response to HMA therapy may be partially driven by T-cell mediated immunity and that the immune-based therapies, which target the adaptive immune system, may play a significant role in select patients with MDS.","prettyUrl":"abbas-2021-fi","following":false,"created":"03/15/2021","featured":false,"publishedDate":"03/15/2021","urlOrId":"abbas-2021-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5d8ddcab-5cd5-4a16-ac94-eb4a277c6831","title":"Bruton’s Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis","investigator":"Bonami, Rachel H.","investigatorInstitution":"Departments of Medicine, Pathology, Microbiology and Immunology, Vanderbilt University","publicationName":"Frontiers in Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"191":"bonami-2021-biorxiv"},"prettyUrlList":["bonami-2021-biorxiv"],"summary":"Bruton’s tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity.  Commensal microbes are essential for arthritis in K/BxN mice, used here to examine how BTK-mediated signaling interfaces with the microbiome.  Btk-deficient K/BxN mice were found to have small Peyer’s Patches with reduced germinal center and IgA+ B cells.  Although lamina propria IgA+ plasma cells were numerically normal, intestinal IgA was low and IgA coating of commensal bacteria was reduced.  IgA-seq showed a shift in microbes that are normally IgA-coated into the uncoated fraction in Btk-deficient mice.  In this altered microbial milieau, the proportion of Parabacteroides distasonis was reduced in Btk-deficient K/BxN mice.  To determine whether P. distasonis contributes to arthritis, it was reintroduced into antibiotic-protected K/BxN mice, where it restored disease. This suggests that P. distasonis’ inability to thrive in Btk-deficient mice may be a factor in disease protection.  Thus, BTK supports normal intestinal IgA development, with downstream effects on the microbiome that may contribute to autoimmunity.","prettyUrl":"bonami-2021-biorxiv","following":false,"created":"03/15/2021","featured":false,"publishedDate":"03/15/2021","urlOrId":"bonami-2021-biorxiv","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"96f46797-219a-44bc-a98a-27e4ad7ea311","title":"Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features","investigator":"Zhang, Jianjun","investigatorInstitution":"Departments of Genomic Medicine and Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"190":"dejima-2021-nc"},"prettyUrlList":["dejima-2021-nc"],"summary":"Coming soon...","prettyUrl":"dejima-2021-nc","following":false,"created":"03/04/2021","featured":false,"publishedDate":"03/04/2021","urlOrId":"dejima-2021-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4429931f-1d19-4a0b-a1b5-5c32c5d2a14d","title":"CD8+ T-cell repertoire in HLA class I-mismatched alloreactive immune response","investigator":"Bettens Florence","investigatorInstitution":"Hopitaux Universitaire de Genéve","publicationName":"Frontiers in Immunology","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"189":"studer-bettens-2020-fi"},"prettyUrlList":["studer-bettens-2020-fi"],"summary":"In transplantation, direct allorecognition is a complex interplay between T-cell receptors (TCR) and HLA molecules and their bound peptides expressed on antigen-presenting cells. In analogy to HLA mismatched hematopoietic stem cell transplantation (HSCT), the TCR CDR3β repertoires of alloreactive cytotoxic CD8+ responder T cells, defined by the cell surface expression of CD137 and triggered in vitro by HLA mismatched stimulating cells, were analyzed in different HLA class I mismatched combinations. The same HLA mismatched stimulatory cells induced very different repertoires in distinct but HLA identical responders. Likewise, stimulator cells derived from HLA identical donors activated CD8+ cells expressing very different repertoires in the same mismatched responder. To mimic in vivo inflammation, expression of HLA class l antigens was upregulated in vitro on stimulating cells by the inflammatory cytokines TNFα and IFNβ. The repertoires differed whether the same responder cells were stimulated with cells treated or not with both cytokines. In conclusion, the selection and expansion of alloreactive cytotoxic T-cell clonotypes expressing a very diverse repertoire is observed repeatedly despite controlling for HLA disparities and is significantly influenced by the inflammatory status. This makes prediction of alloreactive T-cell repertoires a major challenge in HLA mismatched HSCT.In conclusion, the selection and expansion of alloreactive cytotoxic T-cell clonotypes expressing a very diverse repertoire is observed repeatedly despite controlling for HLA disparities and is significantly influenced by the inflammatory status. This makes prediction of alloreactive T-cell repertoires a major challenge in HLA mismatched HSCT.","prettyUrl":"studer-bettens-2020-fi","following":false,"created":"10/29/2020","featured":false,"publishedDate":"03/02/2021","urlOrId":"studer-bettens-2020-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d0a85759-47a3-494f-b452-98c78844c3a3","title":"Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation","investigator":"Fu, Jianing","investigatorInstitution":"Columbia Center for Translational Immunology, Department of Medicine","publicationName":"Journal of Clinical Investigation","researchArea":"Organ transplant","prettyUrls":{"188":"fu-2021-jci"},"prettyUrlList":["fu-2021-jci"],"summary":"In humans receiving intestinal transplantation, long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early post-transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients’ bone marrow (BM) >100 days post-transplant. Individual GvH clones appeared in ileal mucosa or blood before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient antigen-presenting cells into the graft. These results, combined cytotoxic single cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.","prettyUrl":"fu-2021-jci","following":false,"created":"02/17/2021","featured":false,"publishedDate":"03/02/2021","urlOrId":"fu-2021-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bdb58f11-c513-4c72-8154-e071f69b33d7","title":"A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma","investigator":"Konduri, Vanaja","investigatorInstitution":"Department of Pathology & Immunology, Baylor College of Medicine","publicationName":"Science Translational Medicine","researchArea":"Response to Therapeutic Agent","prettyUrls":{"187":"konduri-2021-stm"},"prettyUrlList":["konduri-2021-stm"],"summary":"In humans, the natural killer (NK) cell marker CD161 identifies several subsets of T cells, including a polyclonal CD8 αβ T cell receptor-expressing subset with characteristic specificity for tissue-localized viruses. This subset also displays enhanced cytotoxic and memory phenotypes. Here, we characterized this unique T cell subset and determined its potential suitability for use in chimeric antigen receptor (CAR) T cell therapy. In mice, gene expression profiling among the CD161-equivalent CD8+ T cell populations (CD8+NK1.1+) revealed substantial up-regulation of granzymes, perforin, killer lectin-like receptors, and innate signaling molecules in comparison to CD8+NK1.1- T cells. Adoptive transfer of CD8+NK1.1+ cells from previously exposed animals offered substantially enhanced protection and improved survival against melanoma tumors and influenza infection compared to CD8+NK1.1- cells. Freshly isolated human CD8+CD61+ T cells exhibited heightened allogeneic killing activity in comparison to CD8+CD61- T cells or total peripheral blood mononuclear cells (PBMCs). To determine whether this subset might improve the antitumor efficacy of CAR T cell therapy against solid tumors, we compared bulk PBMCs, CD8+CD161-, and CD8+CD161+ T cells transduced with a human epidermal growth factor receptor-2 (HER2)-specific CAR construct. In vitro, CD8+CD161+ CAR-transduced T cells killed HER2+ targets faster and with greater efficiency. Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2+ pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.","prettyUrl":"konduri-2021-stm","following":false,"created":"02/23/2021","featured":false,"publishedDate":"02/23/2021","urlOrId":"konduri-2021-stm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"726e6200-7a43-4771-9204-bfd912720f64","title":"VJ segment usage of TCR-Beta repertoire in monozygotic cystic fibrosis twins","investigator":"Tümmler, Burkhard","investigatorInstitution":"Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany","publicationName":"Frontiers in Immunology","researchArea":"Basic Immunology","prettyUrls":{"186":"fischer-2021-fi"},"prettyUrlList":["fischer-2021-fi"],"summary":"Sixteen monozygotic cystic fibrosis (CF) twin pairs of whom 14 pairs were homozygous for the most common p.Phe508del CFTR mutation were selected from the European Cystic Fibrosis Twin and Sibling Study Cohort. The monozygotic twins were examined in their T cell receptor (TCR) repertoire in peripheral blood by amplicon sequencing of the CDR3 variable region of the ß-chain. The recruitment of TCR J and V genes for recombination and selection in the thymus showed a strong genetic influence in the CF twin cohort as indicated by the shortest Jensen-Shannon distance to the twin individual. Exceptions were the clinically most discordant and/or most severely affected twin pairs where clonal expansion probably caused by recurrent pulmonary infections overshadowed the impact of the identical genomic blueprint. In general the Simpson clonality was low indicating that the population of TCRß clonotypes of the CF twins was dominated by the naïve T-cell repertoire. Intrapair sharing of clonotypes was significantly more frequent among monozygotic CF twins than among pairs of unrelated CF patients. Complete nucleotide sequence identity was observed in about 0.11% of CDR3 sequences which partially should represent persisting fetal clones derived from the same progenitor T cells. Complete amino acid sequence identity was noted in 0.59% of clonotypes. Of the nearly 40,000 frequent amino acid clonotypes shared by at least two twin siblings 99.8% were already known within the immuneACCESS database and only 73 had yet not been detected indicating that the CDR3ß repertoire of CF children and adolescents does not carry a disease-specific signature but rather shares public clones with that of the non-CF community. Clonotypes shared within twin pairs and between unrelated CF siblings were highly abundant among healthy non-CF people, less represented in individuals with infectious disease and uncommon in patients with cancer. This subset of shared CF clonotypes defines CDR3 amino acid sequences that are more common in health than in disease.","prettyUrl":"fischer-2021-fi","following":false,"created":"02/09/2021","featured":false,"publishedDate":"02/15/2021","urlOrId":"fischer-2021-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"cbe97c48-8bc2-4aba-9028-50a3593eea44","title":"The  immune suppressive microenvironment affects efficacy of  radio-immunotherapy in brain metastasis","investigator":"Niesel, Katja","investigatorInstitution":"Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy","publicationName":"EMBO Molecular Medicine","researchArea":"Cancer","prettyUrls":{"185":"niesel-2021-embomm"},"prettyUrlList":["niesel-2021-embomm"],"summary":"The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastasis. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.","prettyUrl":"niesel-2021-embomm","following":false,"created":"02/12/2021","featured":false,"publishedDate":"02/15/2021","urlOrId":"niesel-2021-embomm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b9c411fe-a1d7-4f2d-9df2-7450cf38cc42","title":"T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors","investigator":"Ito, Fumito","investigatorInstitution":"Roswell Park Comprehensive Cancer Center","publicationName":"Nature Communications","researchArea":"Response to Therapeutic Agent","prettyUrls":{"184":"yamauchi-icb-2021"},"prettyUrlList":["yamauchi-icb-2021"],"summary":"Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers;\nhowever, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.","prettyUrl":"yamauchi-icb-2021","following":false,"created":"02/04/2021","featured":false,"publishedDate":"02/04/2021","urlOrId":"yamauchi-icb-2021","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"52dc9f7c-be6d-4421-aef7-e4d42915506d","title":"Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells","investigator":"Weinberg, Andrew","investigatorInstitution":"Earle A. Chiles Research Institute, Providence Cancer Institute","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"183":"duhen-2020-nc"},"prettyUrlList":["duhen-2020-nc"],"summary":"Despite the success of checkpoint blockade in some cancer patients, there is an unmet need to improve outcomes. Targeting alternative pathways, such as costimulatory molecules (e.g. OX40, GITR, and 4-1BB), can enhance T cell immunity in tumor-bearing hosts. Here we describe the results from a phase Ib clinical trial (NCT02274155) in which 17 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) received a murine anti-human OX40 agonist antibody (MEDI6469) prior to definitive surgical resection. The primary endpoint was to determine safety and feasibility of the anti-OX40 neoadjuvant treatment. The secondary objective was to assess the effect of anti-OX40 on lymphocyte subsets in the tumor and blood. Neoadjuvant anti-OX40 was well tolerated and did not delay surgery, thus meeting the primary endpoint. Peripheral blood phenotyping data show increases in CD4+ and CD8+ T cell proliferation two weeks after anti-OX40 administration. Comparison of tumor biopsies before and after treatment reveals an increase of activated, conventional CD4+ tumor-infiltrating lymphocytes (TIL) in most patients and higher clonality by TCRb sequencing. Analyses of CD8+ TIL show increases in tumor-antigen reactive, proliferating CD103+CD39+ cells in 25% of patients with evaluable tumor tissue (N=4/16), all of whom remain disease-free.\nThese data provide evidence that anti-OX40 prior to surgery is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity. These data provide evidence that anti-OX40 administered in the neoadjuvant setting is safe and can increase activation and proliferation of CD4+ and CD8+ T cells in blood and tumor. Our work suggests that increases in the tumor-reactive CD103+CD39+ CD8+ TIL could serve as a potential biomarker of anti-OX40 clinical activity.","prettyUrl":"duhen-2020-nc","following":false,"created":"02/02/2021","featured":false,"publishedDate":"02/02/2021","urlOrId":"duhen-2020-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"063efde8-3071-43b9-b327-83e42ffa5ef2","title":"A vaccine targeting mutant IDH1 in newly diagnosed glioma","investigator":"Michael, Platten","investigatorInstitution":"CCU Neuroimmunology, German Cancer Research Center","publicationName":"Nature","researchArea":"Vaccine efficacy","prettyUrls":{"182":"platten-2021-nature"},"prettyUrlList":["platten-2021-nature"],"summary":"Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.","prettyUrl":"platten-2021-nature","following":false,"created":"02/02/2021","featured":false,"publishedDate":"02/02/2021","urlOrId":"platten-2021-nature","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"83168555-cff7-4274-bbf4-3fda70c75b4a","title":"Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer","investigator":"Foord, Emelie","investigatorInstitution":"Department of Clinical Science, Intervention and Technology","publicationName":"Science Translational Medicine","researchArea":"Cancer","prettyUrls":{"181":"foord-2020-stm"},"prettyUrlList":["foord-2020-stm"],"summary":"The role of γδ T cells in antitumor immunity has been under investigation for the past two decades, but little is known about their contribution to clinical outcomes in patients. Here, we set out to define the clonotypic, phenotypic, and functional features of γδ T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the γ chain revealed that tumor-infiltrating γδ T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived γδ T cells presented a lower TCR diversity and higher clonality, suggesting a TCR-dependent clonal focusing at this site. Further investigation showed that tumor samples had abundant γδ T cells with a tissue-resident, activation-associated phenotype, less usage of Vγ9 and an impaired response to adaptive-associated stimuli, implying an innate-like activation pathway, rather than an adaptive TCR-engaging pathway, at these tumor sites. Furthermore, high γδ T cell cytokine responsiveness upon stimulation was associated with a favorable outcome for patients in terms of both overall survival and reduced residual tumor burden after primary surgery. Last, the functionality of γδ T cells and patient survival were negatively affected by the proportions of CD39-expressing T cells, highlighting the potential of CD39 as a target to improve γδ T cell responses and unleash their antitumor capabilities.","prettyUrl":"foord-2020-stm","following":false,"created":"11/02/2020","featured":false,"publishedDate":"01/21/2021","urlOrId":"foord-2020-stm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c590809f-e88e-4310-842d-82659bc480c5","title":"Safety and efficacy of consolidation therapy with ipilimumab plus nivolumab after autologous stem cell transplantation","investigator":"Skarbnik, Alan P","investigatorInstitution":"Novant Health Cancer Institute","publicationName":"Transplantation and Cellular Therapy","researchArea":"Cancer Immunotherapy","prettyUrls":{"180":"skarbnik-2020-tct"},"prettyUrlList":["skarbnik-2020-tct"],"summary":"Background: Autologous hematopoietic stem cell transplantation (ASCT) is a standard-of-care treatment for many hematological malignancies. Progression of disease after ASCT is the primary cause of treatment failure. \n\nObjective: In this Phase Ib trial, we studied the safety and clinical effect of combined checkpoint inhibition with ipilimumab and nivolumab as a consolidation strategy after ASCT for patients with high-risk diffuse large B-cell Lymphoma (DLBCL), mature T-cell lymphoma (TCL) and multiple myeloma (MM). Study Design: Starting 14-28 days after ASCT, patients received ipilimumab (1 mg/kg, intravenous, on day 1 of weeks 1, 4, 7, 10, 16, 22) and nivolumab (3 mg/kg, intravenous, on day 1 of weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26). \n\nResults: Patients received a median of five doses of ipilimumab and eight doses of nivolumab. Thirty-five patients were included in the intent-to-treat population. Ninety-four percent of patients experienced immune-related adverse events (irAEs) of any grade. Ninety-seven percent of irAEs resolved spontaneously or by holding study drugs and instituting high-dose corticosteroid therapy. Progression-free and overall survival at 18 months post-ASCT for each disease cohort were, respectively: primary refractory DLBCL, 85.7% and 100%; relapsed DLBCL, 28.6% and 57.1%; frontline TCL: Not Evaluable and 80%; relapsed TCL, 25% and 75%; high-risk transplantnaïve MM, 57.1% and 87% and MM relapsed within 3 years of first ASCT, 40% and 100%. \n\nConclusion: We conclude that combined checkpoint inhibition appears tolerable as a consolidation strategy after ASCT and in addition to the potential clinical efficacy observed in some subsets of disease, T cell receptor repertoire, Tregulatory phenotype and gut microbiota profiles provide a biologic rationale warranting further study of this approach.","prettyUrl":"skarbnik-2020-tct","following":false,"created":"01/08/2021","featured":false,"publishedDate":"01/15/2021","urlOrId":"skarbnik-2020-tct","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a97ed8a3-ca37-46c4-b449-bf119dfc9d8a","title":"Distinct T cell receptor repertoire diversity of clinically defined high-grade serous ovarian cancer treatment subgroups","investigator":"Lee, Sanghoon","investigatorInstitution":"Department of Systems Biology, The University of Texas MD Anderson Cancer Center","publicationName":"iScience","researchArea":"Cancer","prettyUrls":{"179":"sanghoon-2021-iscience"},"prettyUrlList":["sanghoon-2021-iscience"],"summary":"In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n=90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 group than in the NACT group. We found enrichment of specific TCRβ genes usage, as well as distinct mutual exclusiveness and co-occurrence pattern of TCRβ genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens and between copy number variations and mutation load in the groups.","prettyUrl":"sanghoon-2021-iscience","following":false,"created":"06/09/2020","featured":false,"publishedDate":"01/11/2021","urlOrId":"sanghoon-2021-iscience","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"08ff60f1-9b49-4637-a328-1a6590f0c4f3","title":"Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy","investigator":"Turk, Mary Jo","investigatorInstitution":"Geisel School of Medicine at Dartmouth","publicationName":"Nature Cancer","researchArea":"Cancer Immunotherapy","prettyUrls":{"178":"han-2021-natcancer"},"prettyUrlList":["han-2021-natcancer"],"summary":"While T-cell responses to cancer immunotherapy have been avidly studied, long-lived 34 memory has been poorly characterized. In a cohort of metastatic melanoma survivors with exceptional responses to immunotherapy, we probed memory CD8+ 35 T-cell responses across 36 tissues, and across several years. Single-cell RNA sequencing revealed three subsets of resident 37 memory T (TRM) cells shared between tumors and distant vitiligo-affected skin. Paired T-cell 38 receptor sequencing further identified clonotypes in tumors that co-existed as TRM in skin and as 39 effector memory T (TEM) cells in blood. Clonotypes that dispersed throughout tumor, skin, and 40 blood preferentially expressed a IFNG / TNF-high signature, which had a strong prognostic value 41 for melanoma patients. Remarkably, clonotypes from tumors were found in patient skin and 42 blood up to nine years later, with skin maintaining the most focused tumor-associated clonal 43 repertoire. These studies reveal that cancer survivors can maintain durable memory as functional, 44 broadly-distributed TRM and TEM compartments.","prettyUrl":"han-2021-natcancer","following":false,"created":"01/05/2021","featured":false,"publishedDate":"01/06/2021","urlOrId":"han-2021-natcancer","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3c521221-d6b2-4ea3-b8f6-cc7869e5e6f5","title":"Broadly reactive human CD4+ T cells against Enterobacteriaceae are found  in the naïve repertoire and are clonally expanded in the memory repertoire","investigator":"Sallusto, Federica","investigatorInstitution":"Institute for Research in Biomedicine","publicationName":"European Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"177":"cassotta-2020-eji"},"prettyUrlList":["cassotta-2020-eji"],"summary":"Enterobacteriaceae are a large family of Gram-negative bacteria that includes both commensals and opportunistic pathogens. The latter can cause severe nosocomial infections, with outbreaks of multi-antibiotics resistant strains, thus being a major public health threat. In this study, we report that Enterobacteriaceae-reactive memory Th cells were highly enriched in a CCR6+ CXCR3+ Th1*/17 cell subset and produced IFN-γ, IL-17A, and IL-22. This T cell subset was severely reduced in septic patients with K. pneumoniae bloodstream infection who also selectively lacked circulating K. pneumonie-reactive T cells. By combining heterologous antigenic stimulation, single cell cloning and TCR Vβ sequencing, we demonstrate that a large fraction of memory Th cell clones was broadly cross-reactive to several Enterobacteriaceae species. These cross-reactive Th cell clones were expanded in vivo and a large fraction of them recognized the conserved outer membrane protein A antigen. Interestingly, Enterobacteriaceae broadly cross-reactive T cells were also prominent among in vitro primed naïve T cells. Collectively, these data point to the existence of immunodominant T cell epitopes shared among different Enterobacteriaceae species and targeted by cross-reactive T cells that are readily found in the pre-immune repertoire and are clonally expanded in the memory repertoire.","prettyUrl":"cassotta-2020-eji","following":false,"created":"01/04/2021","featured":false,"publishedDate":"01/04/2021","urlOrId":"cassotta-2020-eji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"41bd4c0f-4675-40f4-9a31-8bfcaae8a785","title":"Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial","investigator":"Cascone, Tina","investigatorInstitution":"Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center","publicationName":"Nature Medicine","researchArea":"Other","prettyUrls":{"176":"cascone-2020-nm"},"prettyUrlList":["cascone-2020-nm"],"summary":"Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.","prettyUrl":"cascone-2020-nm","following":false,"created":"09/21/2020","featured":false,"publishedDate":"12/10/2020","urlOrId":"cascone-2020-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7b134d46-565b-4c06-bb4b-d72faaa64881","title":"Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+ T cells in vivo","investigator":"Simonetti, Francesco R.","investigatorInstitution":"Department of Medicine, Johns Hopkins University School of Medicine","publicationName":"Journal of Clinical Investigation","researchArea":"HIV","prettyUrls":{"175":"simonetti-2020-jci"},"prettyUrlList":["simonetti-2020-jci"],"summary":"Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here we show that it is possible to link antigen responsiveness, full proviral sequence, integration site, and T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated Cytomegalovirus (CMV)- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ-integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.","prettyUrl":"simonetti-2020-jci","following":false,"created":"11/20/2020","featured":false,"publishedDate":"12/07/2020","urlOrId":"simonetti-2020-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"407e3aa0-76ad-4286-a8da-555c9a845b1c","title":"Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature","investigator":"Mustjoki, Satu","investigatorInstitution":"University of Helsinki","publicationName":"Frontiers in Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"174":"kelkka-2020-jci"},"prettyUrlList":["kelkka-2020-jci"],"summary":"Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis.\n \nCND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCRβ) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCRβ signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients’ repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing.\n \nOur results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients.","prettyUrl":"kelkka-2020-jci","following":false,"created":"11/13/2020","featured":false,"publishedDate":"11/23/2020","urlOrId":"kelkka-2020-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"946757e6-58e2-4235-b011-58f2599f04e2","title":"Human thymic T cell repertoire is imprinted with strong convergence to shared sequences","investigator":"Arstila, T Petteri","investigatorInstitution":"University of Helsinki","publicationName":"Molecular Immunology","researchArea":"Basic Immunology","prettyUrls":{"173":"heikkila-2020-mi"},"prettyUrlList":["heikkila-2020-mi"],"summary":"A highly diverse repertoire of T cell antigen receptors (TCR) is created in the thymus by recombination of gene segments and the insertion or deletion of nucleotides at the junctions. Using next-generation TCR sequencing we define here the features of recombination and selection in the human TCRα and TCRβ locus, and show that a strikingly high proportion of the repertoire is shared by unrelated individuals. The thymic TCRα nucleotide repertoire was more diverse than TCRβ, with 4.1 × 106 vs. 0.81 × 106 unique clonotypes, and contained nonproductive clonotypes at a higher frequency (69.2% vs. 21.2%). The convergence of distinct nucleotide clonotypes to the same amino acid sequences was higher in TCRα than in TCRβ repertoire (1.45 vs. 1.06 nucleotide sequences per amino acid sequence in thymus). The gene segment usage was biased, and generally all individuals favored the same genes in both TCRα and TCRβ loci. Despite the high diversity, a large fraction of the repertoire was found in more than one donor. The shared fraction was bigger in TCRα than TCRβ repertoire, and more common in in-frame sequences than in nonproductive sequences. Thus, both biases in rearrangement and thymic selection are likely to contribute to the generation of shared repertoire in humans.","prettyUrl":"heikkila-2020-mi","following":false,"created":"11/16/2020","featured":false,"publishedDate":"11/16/2020","urlOrId":"heikkila-2020-mi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"60e6773f-9b9f-47e6-b33a-1532cdc630e3","title":"Exhaustion of tumour-infiltrating T-cell receptor repertoire diversity is an age-dependent indicator of immunological fitness independently predictive of clinical outcome in Burkitt lymphoma","investigator":"Gebauer, Niklas","investigatorInstitution":"Klinik für Hämatologie und Onkologie UKSH Campus Lübeck","publicationName":"British Journal of Haematology","researchArea":"Cancer","prettyUrls":{"172":"rieken-2020-bjh"},"prettyUrlList":["rieken-2020-bjh"],"summary":"Burkitt-lymphoma (BL) is an aggressive-B-cell-malignancy derived from germinal-centre B-cells. Curative therapy traditionally requires intensive immunochemotherapy. Recently, immuno-oncological approaches, modulating the T-cell tumour-response, were approved for the treatment of a variety of malignancies. The architecture of the tumour-infiltrating T-cell-receptor (TCR)-repertoire in BL remains insufficiently characterized.\nWe therefore performed a large-scale, next-generation-sequencing study of the CDR3-region of the TCRβ chain-repertoire in a large cohort of all epidemiological subtypes of BL (n=82) and diffuse large B-cell-lymphoma (DLBCL; n=34). Molecular data were subsequently assessed for correlation with clinical outcome. \nOur investigations revealed an age-dependent immunoprofile in BL similar to DLBCL. Moreover, we found several public clonotypes in numerous patients suggestive of shared tumour-neoantigen selection exclusive to BL and distinct from DLBCL regardless of EBV and/or HIV-status. Compared with baseline, longitudinal analysis unveiled significant repertoire restrictions upon relapse (p=0.0437) while productive-TCR-repertoire clonality proved as a useful indicator of both overall and progression-free-survival (OS: p=0.0001; HR: 6.220; CI: 2.263–11.78; PFS: p=0.0025; HR: 3.086; CI: 1.555–7.030). Multivariate-analysis confirmed its independence from established prognosticators, including age at diagnosis and comorbidities.\nOur findings establish the clinical relevance of the architecture and clonality of the TCR-repertoire and its age-determined dynamics in BL.","prettyUrl":"rieken-2020-bjh","following":false,"created":"11/12/2020","featured":false,"publishedDate":"11/13/2020","urlOrId":"rieken-2020-bjh","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7f60f599-1c4b-4ac7-aca0-d8f30759d05f","title":"Expansion of Human Papillomavirus (HPV)-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed","investigator":"Nakagawa, Mayumi","investigatorInstitution":"Department of Pathology, University of Arkansas for Medical Sciences","publicationName":"Frontiers in Immunology","researchArea":"Response to Therapeutic Agent","prettyUrls":{"171":"shibata-2020-hpv"},"prettyUrlList":["shibata-2020-hpv"],"summary":"Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.","prettyUrl":"shibata-2020-hpv","following":false,"created":"10/30/2020","featured":false,"publishedDate":"11/10/2020","urlOrId":"shibata-2020-hpv","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"eaddbb33-f612-49a5-975f-e5d1daba35af","title":"Permissive HLA-DPB1 mismatches in HCT depend on immunopeptidome divergence and editing by HLA-DM","investigator":"Meurer, Thuja","investigatorInstitution":"Institute for Experimental Cellular Therapy","publicationName":"Blood","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"170":"meurer-2020-blood"},"prettyUrlList":["meurer-2020-blood"],"summary":"In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors (UD) are associated with improved outcomes compared to non-permissive mismatches, but the underlying mechanism is incompletely understood. Here we used mass spectrometry, T-cell receptor-beta (TCR) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared to their non-permissive counterparts, resulting in lower frequency and diversity of alloreactive TCR clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM, or the presence of its antagonist HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT, and show that permissiveness is dependent on HLA-DM-mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.","prettyUrl":"meurer-2020-blood","following":false,"created":"11/09/2020","featured":false,"publishedDate":"11/09/2020","urlOrId":"meurer-2020-blood","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"08e519bc-34a9-4462-8abf-a1c5b957a472","title":"Long-term Sculpting of the B-cell Repertoire Following Cancer Immunotherapy in Patients Treated with Sipuleucel-T","investigator":"Zhang, Li","investigatorInstitution":"Departments of Medicine and Epidemiology & Biostatistics, University of California San Francisco","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"168":"zhang-2020-cir"},"prettyUrlList":["zhang-2020-cir"],"summary":"Sipuleucel-T is an autologous cellular immunotherapy, administered as up to 3 infusions, for metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP) that correlate with improved survival. The long-term impact, however, of sipuleucel-T on tumor antigen-specific immunologic memory remains unknown. In particular, B cell responses as measured by antigen-specific antibody responses and B cell receptor (BCR) sequences remain unknown. To evaluate whether sipuleucel-T can induce long-term immunologic memory, we examined circulating B cell responses before and after sipuleucel-T treatment in two groups of mCRPC patients: those who had previously received sipuleucel-T (treated; median, 8.9 years since the previous treatment) versus those who had not (naïve). Before re-treatment, previously treated patients exhibited persistent antibody responses as well as more focused and convergent BCR repertoires with distinct V(D)J gene usage compared with naïve patients. After retreatment, previously treated patients maintained high frequency clones and developed more convergent BCRs at earlier time points unlike naive patients. With the first sipuleucel-T infusion specifically, previously-treated patients had less shuffling within the 100-most abundant baseline clones whereas, in contrast, naïve patients exhibited great BCR turnover with a continued influx of new B cell clones. Social network analysis showed that previously treated patients had more highly organized B cell repertoires, consistent with greater clonal maturation. Further, higher treatment-induced BCR clonality was correlated with longer survival for naïve patients. These results demonstrate the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B cell repertoire.","prettyUrl":"zhang-2020-cir","following":false,"created":"10/21/2020","featured":false,"publishedDate":"10/22/2020","urlOrId":"zhang-2020-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"71a8dfd3-8611-4d67-9c79-deefc6db37be","title":"immunoSEQ hsTCRB-V4b Control Data","investigator":"Hamm, David","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Controls","prettyUrls":{"169":"tcrbv4-control"},"prettyUrlList":["tcrbv4-control"],"summary":"This data set features 158 Samples with Tissue Source, Indication and Race/Ethnicity information as tags, run on the immunoSEQ hsTCRBv4b Assay. There are 147 peripheral samples (58 PBMC from cancer patients and 88 blood from healthy controls) and 11 FFPE samples (both lung cancer and melanoma).\n\nBlood and PBMC samples were run as deeps with up to 6 ug of DNA for blood samples and up to 2 ug of total DNA for PBMCs.","prettyUrl":"tcrbv4-control","following":false,"created":"10/21/2020","featured":false,"publishedDate":"10/21/2020","urlOrId":"tcrbv4-control","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1a04eec5-9219-443d-8d72-d2f49ff5e102","title":"CRISPR-Cas9-Edited Tacrolimus-Resistant Antiviral T Cells for Advanced Adoptive Immunotherapy in Transplant Recipients","investigator":"Schmueck-Henneresse, Michael","investigatorInstitution":"Charité University Medicine","publicationName":"Molecular Therapy","researchArea":"Organ transplant","prettyUrls":{"167":"amini-2020-mt"},"prettyUrlList":["amini-2020-mt"],"summary":"Viral infections, such as with cytomegalovirus (CMV), remain a major risk factor for mortality and morbidity of transplant recipients because of their requirement for lifelong immunosuppression (IS). Antiviral drugs often cause toxicity and sometimes fail to control disease. Thus, regeneration of the antiviral immune response by adoptive antiviral T cell therapy is an attractive alternative. Our recent data, however, show only short-term efficacy in some solid organ recipients, possibly because of malfunction in transferred T cells caused by ongoing IS. We developed a vector-free clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based good manufacturing practice (GMP)-compliant protocol that efficiently targets and knocks out the gene for the adaptor protein FK506-binding protein 12 (FKBP12), required for the immunosuppressive function of tacrolimus. This was achieved by transient delivery of ribonucleoprotein complexes into CMV-specific T cells by electroporation. We confirmed the tacrolimus resistance of our gene-edited T cell products in vitro and demonstrated performance comparable with non-tacrolimus-treated unmodified T cells. The alternative calcineurin inhibitor cyclosporine A can be administered as a safety switch to shut down tacrolimus-resistant T cell activity in case of adverse effects. Furthermore, we performed safety assessments as a prerequisite for translation to first-in-human applications.","prettyUrl":"amini-2020-mt","following":false,"created":"09/21/2020","featured":false,"publishedDate":"09/21/2020","urlOrId":"amini-2020-mt","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d8fb6de2-d364-4b06-a0d7-0363eb0587cb","title":"Long-term robustness of a T-cell system emerging from somatic rescue of a genetic block in T-cell development","investigator":"Ehl, Stephan","investigatorInstitution":"Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI) and Center for Pediatric and Adolescent Medicine, Medical Center","publicationName":"EBioMedicine","researchArea":"Basic Immunology","prettyUrls":{"166":"kury-2020-ebiomed"},"prettyUrlList":["kury-2020-ebiomed"],"summary":"Backgound: The potential of a single progenitor cell to establish and maintain long-term protective T-cell immunity in humans is unknown. For genetic disorders disabling T-cell immunity, somatic reversion was shown to support limited T-cell development attenuating the clinical phenotype. However, the cases reported so far deteriorated over time leaving unanswered the important question of long-term activity of revertant precursors and the robustness of the resulting T-cell system.\n\nMethods: We applied TCRβ-CDR3 sequencing and mass cytometry on serial samples of a now 18 year-old SCIDX1 patient with somatic reversion to analyse the longitudinal diversification and stability of a T-cell system emerging from somatic gene rescue. \n\nFindings: We detected close to 105 individual CDR3β sequences in the patient. Blood samples of equal size contained about 10-fold fewer unique CDR3β sequences compared to healthy donors, indicating a surprisingly broad repertoire. Despite dramatic expansions and contractions of individual clonotypes representing up to 30% of the repertoire, stable diversity indices revealed that these transient clonal distortions did not cause long-term repertoire imbalance. Phenotypically, the T-cell system did not show evidence for progressive exhaustion. Combined with immunoglobulin substitution, the limited T-cell system in this patient supported an unremarkable clinical course over 18 years.\n\nInterpretation: Genetic correction in the appropriate cell type, in our patient most likely in a T-cell biased self-renewing hematopoietic progenitor, can yield a diverse T-cell system that provides long-term repertoire stability, does not show evidence for progressive exhaustion and is capable of providing protective and regulated T-cell immunity for at least two decades.","prettyUrl":"kury-2020-ebiomed","following":false,"created":"09/09/2020","featured":false,"publishedDate":"09/09/2020","urlOrId":"kury-2020-ebiomed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e5a53393-8bd9-4978-ae4d-84931c7c4ca6","title":"Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients","investigator":"Chow, Jacky","investigatorInstitution":"Roswell Park Comprehensive Cancer Center","publicationName":"PNAS","researchArea":"Cancer","prettyUrls":{"165":"chow-2020-pnas"},"prettyUrlList":["chow-2020-pnas"],"summary":"Clinical studies combining radiation and immunotherapy have shown promising response rates, strengthening efforts to sensitize tumors to immune-mediated attack. Thus, there is an ongoing surge in trials using preconditioning regimens with immunotherapy. Yet, due to the scarcity of resected tumors treated in situ with radiotherapy, there has been little investigation of radiation’s sole contributions to local and systemic antitumor immunity in patients. Without this access, translational studies have been limited to evaluating circulating immune subsets and systemic remodeling of peripheral T cell receptor repertoires. This constraint has left gaps in how radiation impacts intratumoral responses and whether tumor-resident T cell clones are amplified following treatment. Therefore, to interrogate the immune impact of radiation on the tumor microenvironment and test the hypothesis that radiation initiates local and systemic expansion of tumor-resident clones, we analyzed renal cell carcinomas from patients treated with stereotactic body radiation therapy. Transcriptomic comparisons were evaluated by bulk RNA sequencing. T cell receptor sequencing monitored repertoires during treatment. Pathway analysis showed radiation-specific enrichment of immune-related processes, and T cell receptor sequencing revealed increased clonality in radiation-treated tumors. The frequency of identified, tumor-enriched clonotypes was tracked across serial blood samples. We observed increased abundance of tumor-enriched clonotypes at 2 wk postradiation compared with pretreatment levels; however, this expansion was not sustained, and levels contracted toward baseline by 4 wk post treatment. Taken together, these results indicate robust intratumoral immune remodeling and a window of tumor-resident T cell expansion following radiation that may be leveraged for the rational design of combinatorial strategies.","prettyUrl":"chow-2020-pnas","following":false,"created":"08/21/2020","featured":false,"publishedDate":"09/08/2020","urlOrId":"chow-2020-pnas","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b26fb32b-6add-49bc-8523-9f49eb930762","title":"A Peripheral Immune Signature of Responsiveness to PD-1 Blockade in Patients with Classical Hodgkin Lymphoma","investigator":"Cader, Fathima Zumla","investigatorInstitution":"Department of Medical Oncology","publicationName":"Nature Medicine","researchArea":"Cancer","prettyUrls":{"163":"cader-2020-nm"},"prettyUrlList":["cader-2020-nm"],"summary":"PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs) which exhibit frequent chromosome 9p24.1/CD274 (PD-L1)/PDC1LG2 (PD-L2) copy gains. However, in this largely MHC class I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T-cell receptor (TCR) sequencing and cytometry by time-of-flight analysis (CyTOF) to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4+, but not CD8+, TCR diversity significantly increased during therapy, most strikingly in patients who achieved complete responses. Additionally, responding patients had an increased abundance of activated NK cells and a newly identified CD3-CD68+CD4+GrB+ subset. These studies highlight the roles of recently expanded, clonally diverse CD4+ T cells and innate effectors in the efficacy of PD-1 blockade in cHL.","prettyUrl":"cader-2020-nm","following":false,"created":"08/04/2020","featured":false,"publishedDate":"08/05/2020","urlOrId":"cader-2020-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d47e5ad9-51b8-4f78-9a30-1b615ff36bde","title":"A large-scale database of T-cell receptor beta (TCRb) sequences and binding associations from  natural and synthetic exposure to SARS-CoV-2","investigator":"Robins, Harlan","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Infectious Disease","prettyUrls":{"162":"covid-2020"},"prettyUrlList":["covid-2020"],"summary":"We describe the establishment and current content of the ImmuneCODE&trade; database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 160,000 high-confidence SARS-CoV-2-specific TCRs.\n\nThis database is made freely available, and the data contained in it can be analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.  Use the <b>\"Open in Analyses\"</b> link now to explore the immune profile of ImmuneCODE subjects in immunoSEQ&reg; Analyzer.\n\n<b>Download</b> the latest ImmuneCODE datasets here:<ul style=\"list-style-type:disc;\"><li>Release 002 - 1,414 subjects exposed to or infected with the SARSCoV-2 virus: <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoires-002.tgz\">ImmuneCODE-Repertoires-002.tgz</a> (23.8 GB)</li><li>Release 002 - sample metadata: <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoire-Tags-002.2.tsv\">ImmuneCODE-Repertoire-Tags-002.2.tsv</a> (572 KB)</li><li>Release 002.1 - over 160,000 high-confidence SARS-CoV-2-specific TCRs: <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-MIRA-Release002.1.zip\">ImmuneCODE-MIRA-Release002.1.zip</a> (3.7 MB)</li><li>Release 002.2 - additional 72 subjects exposed to or infected with the SARSCoV-2 virus: <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoires-002.2.tgz\">ImmuneCODE-Repertoires-002.2.tgz</a> (1 GB)</li><li>Release 002.2 - sample metadata: <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoire-Tags-002.2.xlsx\">ImmuneCODE-Repertoire-Tags-002.2.xlsx</a> (352 KB)</li></ul>\nWith the immunoSEQ&reg; T-MAP&trade; COVID tools you can analyze and study the SARS-CoV-2-specific antigen and TCR data in the ImmuneCODE database. Use the \"Open in Analyses\" link above then choose \"COVID Search Tool\" from the Tools menu to explore the dataset.\n\nUse of the ImmuneCODE database is subject to <a href=\"https://clients.adaptivebiotech.com/terms-of-use\" target=\"_blank\">Terms of Use</a>.  Full text of this manuscript is available at <a href=\"https://www.researchsquare.com/article/rs-51964/v1\" target=\"_blank\">https://www.researchsquare.com/article/rs-51964/v1</a>.\n\nThe following files have been superceded but remain available for archival purposes:<ul style=\"list-style-type:disc;\"><li><a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-MIRA-Release002.zip\">ImmuneCODE-MIRA-Release002.zip (3.0 MB)</a></li><li><a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoire-Tags-002.tsv\">ImmuneCODE-Repertoire-Tags-002.tsv (514 KB)</a></li><li><a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/covid-2020/ImmuneCODE-Repertoire-Tags-002.xlsx\">ImmuneCODE-Repertoire-Tags-002.xlsx (327 KB)</a></li></ul>","prettyUrl":"covid-2020","following":false,"created":"07/29/2020","featured":true,"publishedDate":"07/29/2020","urlOrId":"covid-2020","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2fd28c22-fca0-4d1e-807c-81f0d9b164d9","title":"T cell receptor diversity and lineage relationship between virus-specific CD8 T cell subsets during chronic LCMV infection","investigator":"Ahmed, Rafi","investigatorInstitution":"Emory University","publicationName":"Journal of Virology","researchArea":"Basic Immunology","prettyUrls":{"161":"chang-2020-jv"},"prettyUrlList":["chang-2020-jv"],"summary":"Recent studies on chronic viral infections have defined a novel PD-1+ TCF1+ stem-like CD8 T cell subset that gives rise to the terminally differentiated exhausted CD8 T cells.  In this study, we performed T cell receptor (TCR)β sequencing of virus-specific CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection to examine the TCR diversity and lineage relationship of these two functionally distinct subsets. We found that >95% of the TCR repertoire of the exhausted CD8 T cell subset was shared with the stem-like CD8 T cells. The TCR repertoires of both CD8 T cell subsets were composed mostly of a few dominant clonotypes but there was slightly more breadth and diversity in the stem-like CD8 T cells compared to their exhausted counterpart (~40 versus ~15 GP33+ clonotypes; ~20 versus ~7 GP276+ clonotypes). Interestingly, the breadth of the TCR repertoire was broader during the early stages (day 8)  of the chronic infection compared to the later stages (day 45-60) showing that there was a narrowing of the TCR repertoire during chronic infection (~2-fold GP33+ and GP276+ stem-like subset; ~10-fold GP33+ and ~5-fold GP276+ exhausted subset).  In contrast, during acute LCMV infection the TCR repertoire was much broader in both GP33-specific effector (~160 clonotypes) and memory CD8 T cells (~160 clonotypes).  Overall, our data demonstrate that the virus-specific CD8 T cell TCR repertoire is broad and remains stable after acute LCMV infection, but it contracts and is narrower during chronic infection. Our study also shows that the repertoire of the exhausted CD8 T cell subset is almost completely derived from the stem-like CD8 T cell subset during established chronic LCMV infection.","prettyUrl":"chang-2020-jv","following":false,"created":"07/24/2020","featured":false,"publishedDate":"07/27/2020","urlOrId":"chang-2020-jv","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"035d467c-24e0-44c1-8e40-19d75d7495e6","title":"Differential skewing of donor-unrestricted and gd T cell repertoires in tuberculosis-infected human lungs","investigator":"Behar, Samuel M.","investigatorInstitution":"Department of Microbiology and Physiological Systems, University of Massachusetts Medical School","publicationName":"Journal of Clinical Investigation","researchArea":"Infectious Disease","prettyUrls":{"160":"ogongo-2020-jci"},"prettyUrlList":["ogongo-2020-jci"],"summary":"Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1- restricted T cells, and γδ T cells. We exploited the distinctive nature of DURTs and γδ T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCRs in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCRδ repertoire, in contrast, was highly skewed in the lungs, where it was dominated by Vδ1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident γδ T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease.","prettyUrl":"ogongo-2020-jci","following":false,"created":"07/09/2020","featured":false,"publishedDate":"07/10/2020","urlOrId":"ogongo-2020-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7b9656be-2520-473e-ad7a-9e38b217a46f","title":"Autoreactivity in naïve human fetal B cells is associated with commensal bacteria recognition","investigator":"Chen, Jeff W.","investigatorInstitution":"Department of Immunobiology","publicationName":"Science","researchArea":"Autoimmune Disorders","prettyUrls":{"159":"chen-2020-science"},"prettyUrlList":["chen-2020-science"],"summary":"Restricted V(D)J recombination during fetal development was postulated to limit antibody repertoire breadth and prevent autoimmunity. However, newborn serum contains abundant autoantibodies, suggesting that B cell tolerance during gestation is not yet fully established. To investigate this apparent paradox, we evaluated the reactivities of over 500 antibodies cloned from single B cells from human fetal liver, bone marrow, and spleen. We found that incomplete B cell tolerance in early human fetal life favored the accumulation of polyreactive B cells that bound both apoptotic cells and commensal bacteria from healthy adults. Thus, the restricted fetal pre-immune repertoire contains potentially beneficial self-reactive innate-like B cell specificities that may facilitate the removal of apoptotic cells during development and shape gut microbiota assembly after birth.","prettyUrl":"chen-2020-science","following":false,"created":"07/01/2020","featured":false,"publishedDate":"07/01/2020","urlOrId":"chen-2020-science","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4c601940-904e-4b9f-9441-f495a4065eea","title":"Cancer cell CCR2 orchestrates suppression of the adaptive immune response","investigator":"Egeblad, Mikala","investigatorInstitution":"Cold Spring Harbor Laboratory","publicationName":"Journal of Experimental Medicine","researchArea":"Cancer","prettyUrls":{"158":"fein-2020-jem"},"prettyUrlList":["fein-2020-jem"],"summary":"C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and ~2-fold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as upregulation of MHC class I and downregulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2-/- cancer cells did not induce immune suppression in Batf3-/- mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.","prettyUrl":"fein-2020-jem","following":false,"created":"06/26/2020","featured":false,"publishedDate":"06/26/2020","urlOrId":"fein-2020-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"850ade6d-4524-4a2a-ad7f-21f535e6bfd3","title":"High frequency of shared clonotypes in human T cell receptor repertoires","investigator":"Soto, Cinque","investigatorInstitution":"Vanderbilt Vaccine Center and Department of Pediatrics","publicationName":"Cell Reports","researchArea":"Basic Immunology","prettyUrls":{"157":"soto-2020-cr"},"prettyUrlList":["soto-2020-cr"],"summary":"The size of the collection of T cell receptors (TCR) generated by recombination of variable, diversity and joining gene segments combined with non-templated junctional additions is large but unknown. We generated very large TCR repertoire datasets as a resource to facilitate detailed studies of the role of TCR clonotypes and repertoires in health and disease. As a demonstration of the utility of the data, we estimated the size of individual human recombined and expressed T cell receptor gene repertoires by TCRA and TCRB gene sequence analysis at unprecedented depth and determined the extent of shared repertoire between individuals. It is not previously established at this depth of sequencing the degree to which individuals possess mostly unique or shared repertoires. Here, the experiments revealed that each individual’s blood sample contained between 5 and 21 million TCR clonotypes. Three individuals shared 8% of TCRβ or 11% of TCRA chain clonotypes. Sorting by T cell phenotypes in four individuals showed that 5% of the CD4+ and 3.5% of CD8+ naïve subsets shared their TCRβ clonotypes. The memory CD4+ and CD8+ subsets shared 2.3% and 0.4% of their clonotypes. We observed a high prevalence of shared clonotypes at this depth of sequencing in both naïve and memory T cell repertoires, and identified the sequences of these shared TCR clonotypes, which is of broad interest for studies of human T cell biology and responses.","prettyUrl":"soto-2020-cr","following":false,"created":"06/05/2020","featured":false,"publishedDate":"06/06/2020","urlOrId":"soto-2020-cr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7d742a21-6978-41c5-91a5-d43819011606","title":"T-cell  Repertoire in Combination with T-cell Density Predicts Clinical Outcomes in Patients with Merkel Cell Carcinoma","investigator":"Tetzlaff, Michael T.","investigatorInstitution":"Department of Pathology and Laboratory Medicine; Department of Translational and Molecular Pathology","publicationName":"Journal of Investigative Dermatology","researchArea":"Cancer","prettyUrls":{"155":"farah-2020-jid"},"prettyUrlList":["farah-2020-jid"],"summary":"The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma (MCC). Higher density of tumor-associated T cells correlates with improved MCC-specific survival, but the prognostic importance of the T cell infiltrate reactivity is unknown. We evaluated the T cell receptor (TCR) repertoire associated with 72 primary MCCs and correlated metrics of the TCR repertoire with clinicopathologic characteristics and patient outcomes.","prettyUrl":"farah-2020-jid","following":false,"created":"05/04/2020","featured":false,"publishedDate":"05/04/2020","urlOrId":"farah-2020-jid","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2b28eb64-8a15-498e-86e0-5830c0ba73dc","title":"Differential lymphopenia induced by photon vs proton based radiotherapy","investigator":"Heather, James","investigatorInstitution":"Massachusetts General Hospital Cancer Center","publicationName":"","researchArea":"Cancer","prettyUrls":{"154":"heather-2020"},"prettyUrlList":["heather-2020"],"summary":"Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy – which accounts for the vast majority – is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system-based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. \nIn this study we aimed to investigate the exact nature of the differential impact of the two radiation modalities upon the immune system. Using multiparametric flow cytometry and deep sequencing of rearranged TCRb loci in a cohort of 20 patients with varying tumors, we explore the nature of the radiation-immune dysregulation. Proton-treated patients remained relatively stable across treatment for most metrics considered, whereas those who received photons saw a profound depletion in naïve T cells, increase in effector/memory populations, and loss of TCR diversity. After hitting their lymphocyte count nadir photon-treated patients saw oligoclonal expansion, particularly of CD8+ Temra cells, driving this reduction in diversity. \nAcross the entire cohort, this reduction in post-nadir diversity inversely correlated with the overall survival time of those patients who died. This raises the possibility that increased adoption of proton-based (or other lymphocyte sparing) radiotherapies may offer lead to better survival in cancer patients.","prettyUrl":"heather-2020","following":false,"created":"05/01/2020","featured":false,"publishedDate":"05/01/2020","urlOrId":"heather-2020","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"eeb42802-c04b-470c-a528-6d47054c4ef7","title":"Maternal T cells in the Human Placental Villi Support an Allograft Response During Non-Infectious Villitis","investigator":"Enninga, Elizabeth Ann","investigatorInstitution":"Mayo Clinic Rochester","publicationName":"Journal of Immunology","researchArea":"Other","prettyUrls":{"153":"enninga-2020-ji"},"prettyUrlList":["enninga-2020-ji"],"summary":"During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the non-infectious infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. Here we characterized the global T cell receptor (TCR) beta chain profile in human placental T cells diagnosed with VUE compared to control and infectious villitis diagnosed placentae by immunoSEQ. Deep sequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (cytomegalovirus [CMV], Epstein-Barr virus and influenza A) demonstrated that antigen specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE is an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk of VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.","prettyUrl":"enninga-2020-ji","following":false,"created":"03/06/2020","featured":false,"publishedDate":"04/30/2020","urlOrId":"enninga-2020-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d57d8f7e-c2f5-41e8-984c-f97bf7d34a1f","title":"Intratumoral heterogeneity and clonal evolution in liver cancer","investigator":"Villanueva, Augusto","investigatorInstitution":"Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"152":"losic-2020-nc"},"prettyUrlList":["losic-2020-nc"],"summary":"Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.","prettyUrl":"losic-2020-nc","following":false,"created":"04/03/2020","featured":false,"publishedDate":"04/03/2020","urlOrId":"losic-2020-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"28b1b7ff-5c54-4a16-a357-5a9e871f5461","title":"Prevalent and diverse intratumoral oncoprotein-specific CD8 T cells within polyoma virus-driven Merkel cell carcinomas","investigator":"Koelle, David","investigatorInstitution":"University of Washington","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"151":"jing-2020-cir"},"prettyUrlList":["jing-2020-cir"],"summary":"Background: Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. It is rational that strategies to increase CD8 T cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. Methods: We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). Results: TIL from 9 of 12 (75%) subjects contain CD8 T cells recognizing 1 to 8 MCPyV epitopes per person. Analysis of 16 novel MCPyV CD8 TIL epitopes in this report, and prior TIL data, indicate that 97% of MCPyV (+) MCC patients have HLA alleles with the genetic potential that restrict CD8 T cell responses to MCPyV T-Ag. The LT AA 70-110 region is particularly epitope-rich, while the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DC was documented. Conclusions: Recovery of MCPyV oncoprotein-specific CD8 TIL from most tumors indicates that antigen indifference is unlikely to be a major cause of checkpoint inhibition failure. The myriad epitopes restricted by diverse HLA alleles indicate that vaccination is a rational component of immunotherapy if tumor immune suppression can be overcome. The oncogenic regions of T-Ag can be modified without impacting immunogenicity.","prettyUrl":"jing-2020-cir","following":false,"created":"11/11/2019","featured":false,"publishedDate":"03/16/2020","urlOrId":"jing-2020-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c35e8499-d118-4b1d-91f2-84c38c8c2095","title":"Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease","investigator":"Mustjoki, Satu","investigatorInstitution":"Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland","publicationName":"Nature Communications","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"156":"kim-2020-natcomm"},"prettyUrlList":["kim-2020-natcomm"],"summary":"Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4+ T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.","prettyUrl":"kim-2020-natcomm","following":false,"created":"03/14/2020","featured":false,"publishedDate":"03/14/2020","urlOrId":"kim-2020-natcomm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1294962d-8ea2-4b93-9f52-101213dbe3d5","title":"Immuno-genomic landscape of osteosarcoma","investigator":"Futreal, P Andrew","investigatorInstitution":"Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"149":"wu-2020-nc"},"prettyUrlList":["wu-2020-nc"],"summary":"Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neo-antigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.","prettyUrl":"wu-2020-nc","following":false,"created":"03/12/2020","featured":false,"publishedDate":"03/12/2020","urlOrId":"wu-2020-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"485f0fc0-92d5-42ff-a5b4-98a3622f75d1","title":"T cell receptor sequencing-based assay identifies cross-reactive recall CD8+ T cell clonotypes against autologous HIV-1 epitope variants","investigator":"Smith, Kellie","investigatorInstitution":"Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy","publicationName":"Frontiers in Immunology","researchArea":"HIV","prettyUrls":{"148":"chan-2020-fi"},"prettyUrlList":["chan-2020-fi"],"summary":"HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8+ T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches.","prettyUrl":"chan-2020-fi","following":false,"created":"03/11/2020","featured":false,"publishedDate":"03/11/2020","urlOrId":"chan-2020-fi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"aca735a3-2d07-497d-9734-ab66286032df","title":"Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor alpha and beta Repertoires","investigator":"Selin, Liisa","investigatorInstitution":"University of Massachusetts Medical School, Department of Pathology","publicationName":"mBio","researchArea":"Infectious Disease","prettyUrls":{"147":"selin-2020-mbio"},"prettyUrlList":["selin-2020-mbio"],"summary":"Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse “de novo” clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1-109 and BMLF1-280, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRA CDR3 motifs played a dominant role, while TCRB played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported rep- ertoires, which appear to be selected either on TCRB CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRA CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in trans- plant settings or for cancer.","prettyUrl":"selin-2020-mbio","following":false,"created":"02/22/2020","featured":false,"publishedDate":"03/09/2020","urlOrId":"selin-2020-mbio","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"21e616ea-aaf5-4aa7-8301-b64692c46cc2","title":"A phase Ib study of preoperative, locoregional IRX-2 cytokine immunotherapy to prime immune responses in patients with early stage breast cancer","investigator":"Page, David B.","investigatorInstitution":"Earle A. Chiles Research Institute, Providence Cancer Institute","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"146":"page-2019-ccr"},"prettyUrlList":["page-2019-ccr"],"summary":"Purpose: To evaluate the safety and feasibility of pre-operative locoregional cytokine therapy (IRX-2 regimen) in early stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. Experimental Design: Sixteen patients with stage I-III early stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive pre-operative locoregional immunotherapy with the IRX-2 cytokine biologic (2mL subcutaneous x 10 days to peri-areolar skin). The regimen also included single-dose cyclophosphamide (300mg/m2) on day 1 to deplete T-regulatory cells, and oral indomethacin to modulate suppressive myeloid subpopulations. The primary objective was to evaluate feasibility (i.e. receipt of therapy without surgical delays or grade III/IV treatment-related adverse events). The secondary objective was to evaluate changes in stromal tumor infiltrating lymphocyte score. The exploratory objective was to identify candidate pharmacodynamic changes for future study using a variety of assays including flow cytometry, RNA and T-cell receptor DNA sequencing, and multispectral immunofluroescence. Results: Pre-operative locoregional cytokine administration was feasible in 100% (n=16/16) of subjects and associated with increases in stromal tumor-infiltrating lymphocytes (p<.001). Programmed death ligand 1 was upregulated at the RNA (p<.01) and protein level ((by Ventana PD-L1 (SP142) and immunofluorescence). Other immunomodulatory effects included upregulation of RNA signatures of T-cell activation and recruitment, and cyclophosphamide-related peripheral T-regulatory cell depletion. Conclusion: IRX-2 is safe in early stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early stage breast cancer and other malignancies.","prettyUrl":"page-2019-ccr","following":false,"created":"03/05/2020","featured":false,"publishedDate":"03/05/2020","urlOrId":"page-2019-ccr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4ba29465-5aa7-46c3-8181-94b875f22e06","title":"Model to improve specificity for identification of clinically-relevant expanded T cells in peripheral blood","investigator":"Yusko, Erik","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"PLoS One","researchArea":"Other","prettyUrls":{"145":"rytlewski-2019-plos"},"prettyUrlList":["rytlewski-2019-plos"],"summary":"Current methods to quantify T-cell clonal expansion only account for variance due to random sampling from a highly diverse repertoire space. We propose a beta-binomial model to incorporate time-dependent variance into the assessment of differentially abundant T-cell clones, identified by unique T Cell Receptor (TCR) β-chain rearrangements, and show that this model improves specificity for detecting clinically relevant clonal expansion. Using blood samples from ten healthy donors, we modeled the variance of T-cell clones within each subject over time and calibrated the dispersion parameters of the beta distribution to fit this variance. As a validation, we compared pre- versus post-treatment blood samples from urothelial cancer patients treated with atezolizumab, where clonal expansion (quantified by the earlier binomial model) was previously reported to correlate with benefit. The beta-binomial model significantly reduced the false-positive rate for detecting differentially abundant clones over time compared to the earlier binomial method. In the urothelial cancer cohort, the beta-binomial model enriched for tumor infiltrating lymphocytes among the clones detected as expanding in the peripheral blood in response to therapy compared to the binomial model and improved the overall correlation with clinical benefit. Incorporating time-dependent variance into the statistical framework for measuring differentially abundant T-cell clones improves the model's specificity for T-cells that correlate more strongly with the disease and treatment setting of-interest. Reducing background-level clonal expansion, therefore, improves the quality of clonal expansion as a biomarker for assessing the T cell immune response and correlations with clinical measures.","prettyUrl":"rytlewski-2019-plos","following":false,"created":"02/20/2020","featured":false,"publishedDate":"02/20/2020","urlOrId":"rytlewski-2019-plos","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d475b0ed-0bf7-4a58-872f-4bfd55a77dc9","title":"Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitis","investigator":"Lee, Bomi","investigatorInstitution":"Division of Gastroenterology and Hepatology, School of Medicine, Stanford University","publicationName":"Journal of Clinical Investigation","researchArea":"Gastrointestinal","prettyUrls":{"143":"lee-2020-jci"},"prettyUrlList":["lee-2020-jci"],"summary":"Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients that included hereditary and idiopathic CP undergoing total pancreatectomy with islet auto-transplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor beta (TCR beta repertoire in CP and controls. TCR beta-sequencing revealed a significant increase in TCR beta repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in V-J gene family usage between hereditary and idiopathic CP and a positive correlation of TCR beta rearrangements with CP disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreata indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanism of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis providing new insights into immune responses associated with human CP.","prettyUrl":"lee-2020-jci","following":false,"created":"01/30/2020","featured":false,"publishedDate":"02/19/2020","urlOrId":"lee-2020-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c1e97809-dc70-4419-bc75-49df0d2b827a","title":"Immune awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy","investigator":"Valpione, Sara","investigatorInstitution":"Cancer Research UK Manchester Institute","publicationName":"Nature Cancer","researchArea":"Cancer Immunotherapy","prettyUrls":{"142":"valpione-2020-nm"},"prettyUrlList":["valpione-2020-nm"],"summary":"BACKGROUND: Our incomplete understanding of T cell evolution under checkpoint inhibitors (CPI) is still incomplete, restraining the achievement of full benefit from CPI.\nOBJECTIVES: We studied peripheral T cell turnover and evolution and their prognostic value after one cycle of CPI analysing T cell receptor-β (TCR) sequences in plasma cell-free DNA (cfDNA) and PBMC, and performing a phenotypic analysis of peripheral T cell subsets.\nRESULTS: Peripheral T cell turnover and TCR repertoire dynamics correlated with response. Additionally, the cfDNA TCR repertoire reorganisation fingerprint correlated with the expansion of an immune-effector subset of peripheral T cells that predicted treatment response. \nCONCLUSIONS: Prognostic changes in peripheral T cells occur within 3 weeks of commencing CPI treatment. This dynamic immune-awakening can be monitored using minimally invasive liquid biopsies.","prettyUrl":"valpione-2020-nm","following":false,"created":"01/10/2020","featured":false,"publishedDate":"02/14/2020","urlOrId":"valpione-2020-nm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f06168cd-ee60-4174-9444-995b2ec21e2f","title":"Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence","investigator":"Kupper, Thomas S","investigatorInstitution":"Brigham and Women’s Hospital, Department of Dermatology and Harvard Medical School","publicationName":"Nature Cancer","researchArea":"Cancer","prettyUrls":{"141":"pruessmann-2019-nc"},"prettyUrlList":["pruessmann-2019-nc"],"summary":"Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.","prettyUrl":"pruessmann-2019-nc","following":false,"created":"01/19/2020","featured":false,"publishedDate":"01/20/2020","urlOrId":"pruessmann-2019-nc","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c18b5b87-e023-4b99-9f6f-c966fcf32562","title":"Comprehensive T cell repertoire characterization of localized non-small cell lung cancer","investigator":"Reuben, Alexandre","investigatorInstitution":"Departments of Thoracic/Head and Neck Medical Oncology and Surgical Oncology","publicationName":"Nature Communications","researchArea":"Cancer","prettyUrls":{"139":"reuben-2019-natcomms"},"prettyUrlList":["reuben-2019-natcomms"],"summary":"We performed comprehensive T cell repertoire analysis in a cohort of 236 early-stage non-small cell lung cancer (NSCLC) patients. T cell repertoire attributes were associated with tumor clinicopathologic features as well as mutational and immune landscape. A considerable proportion of the most prevalent T cells identified in tumors were also prevalent in the uninvolved tumor-adjacent lung tissues and appeared to be reactive to shared background mutations or viral infections. Importantly, patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibited inferior survival. These findings indicate that a concise understanding of shared antigens and T cells between tumor and uninvolved tumor-adjacent lung tissue in NSCLC is needed to improve therapeutic efficacy and reduce the risk of toxicity in the context of immunotherapy, particularly adoptive T cell therapy.","prettyUrl":"reuben-2019-natcomms","following":false,"created":"12/18/2019","featured":false,"publishedDate":"12/20/2019","urlOrId":"reuben-2019-natcomms","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"79026222-7483-454f-a04f-3d1a615b7619","title":"High PD-L1/CD86 MFI ratio and IL-10 secretion characterize human regulatory dendritic cells generated for clinical testing in organ transplantation","investigator":"Zahorchak, A.F.","investigatorInstitution":"Starzl Transplantation Institute, University of Pittsburgh School of Medicine","publicationName":"Cell Immunology","researchArea":"Organ transplant","prettyUrls":{"137":"zahorchak-2017-ci"},"prettyUrlList":["zahorchak-2017-ci"],"summary":"Human regulatory dendritic cells (DCreg) were generated from CD14 immunobead-purified or elutriated monocytes in the presence of vitamin D3 and IL-10. They exhibited similar, low levels of costimulatory CD80 and CD86, but comparatively high levels of co-inhibitory programed death ligand-1 (PD-L1) and IL-10 production compared to control immature DC (iDC). Following Toll-like receptor 4 ligation, unlike control iDC, DCreg resisted phenotypic and functional maturation and further upregulated PD-L1:CD86 expression. Whereas LPS-stimulated control iDC (mature DC; matDC) secreted pro-inflammatory tumor necrosis factor α but no IL-10, the converse was observed for LPS-stimulated DCreg. DCreg weakly stimulated naïve and memory allogeneic CD4+ and CD8+ T cell proliferation and IFN, IL-17A and perforin/granzyme B production in MLR. Their stimulatory function was enhanced however, by blocking PD-1 ligation. High-throughput T cell receptor (TCR) sequencing revealed that, among circulating T cell subsets, memory CD8+ T cells contained the most alloreactive TCR clonotypes and that, while matDC expanded these alloreactive memory CD8 TCR clonotypes, DCreg were effective at inhibiting their expansion. These findings demonstrate the feasibility of generating highly-purified GMP-grade DCreg for systemic infusion, their ability to regulate the alloreactive T cell repertoire and function, and a key mechanistic role of the PD1 pathway.","prettyUrl":"zahorchak-2017-ci","following":false,"created":"08/02/2017","featured":false,"publishedDate":"12/04/2019","urlOrId":"zahorchak-2017-ci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3eadb05c-be98-42b3-b7c5-7c18798ed1ca","title":"Blood and tissue from two control Balb/c mice","investigator":"Boland, Katie","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Controls","prettyUrls":{"136":"balbc-tissue-controls-2019"},"prettyUrlList":["balbc-tissue-controls-2019"],"summary":"Blood, skin, liver, duodenum, colon, spleen and mesenteric lymph node samples from two control Balb/c mice. Both mice are 10-11 week old females.","prettyUrl":"balbc-tissue-controls-2019","following":false,"created":"11/27/2019","featured":false,"publishedDate":"11/27/2019","urlOrId":"balbc-tissue-controls-2019","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5b1d7d3d-4936-404f-bf32-c08d51c4f1a9","title":"ERG controls B-cell development by promoting Igh V-to-DJ recombination","investigator":"Søndergaard, Elisabeth","investigatorInstitution":"The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen","publicationName":"Cell Reports","researchArea":"Basic Immunology","prettyUrls":{"135":"sondergaard-2019-cr"},"prettyUrlList":["sondergaard-2019-cr"],"summary":"B-cell development is dependent on the coordinated expression and cooperation of several transcription factors. Here, we show that the transcription factor ETS Related Gene (ERG) is crucial for normal B-cell development, and that deletion of this factor results in a substantial loss of bone marrow B-cell progenitors and peripheral B-cells as well as a skewing of splenic B-cell populations. We found that ERG-deficient B-lineage cells exhibited an early developmental block, at the pro- to pre-B stage, and proliferated less. The cells failed to express the immunoglobulin heavy chain due to inefficient V-to-DJ recombination and cells that managed to undergo recombination displayed a strong bias against incorporation of distal V genes. Furthermore, antisense transcription at PAX5-activated intergenic repeat (PAIR) elements located in the distal region of the Igh locus was completely dependent on ERG. These findings identify ERG as a novel critical regulator of B-cell development by ensuring efficient and balanced V-to-DJ recombination.","prettyUrl":"sondergaard-2019-cr","following":false,"created":"11/25/2019","featured":false,"publishedDate":"11/25/2019","urlOrId":"sondergaard-2019-cr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ff0df083-dd19-4db9-94f7-67ffd27d2396","title":"CD8+γδ T cells are more frequent in CMV seropositive bone marrow grafts and display phenotype of an adaptive immune response","investigator":"Arruda, Lucas CM","investigatorInstitution":"Department of Clinical Science, Intervention and Technology, Karolinska Institutet","publicationName":"Stem Cell International","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"133":"gaballa-2019-sci"},"prettyUrlList":["gaballa-2019-sci"],"summary":"The role of gamma delta (γδ) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of γδ T cells in response to HCMV, shedding light on the adaptive immune response of γδ T cells. Nevertheless, most efforts have focused on Vδ2neg γδ T cell subset while less attention has been given to investigate other less common γδ T cell subsets. In this regard, an unusual subpopulation of γδ T cells that express the CD8 co-receptor (CD8+γδ T cells) has been shown to be a developmentally and functionally distinct subset. However, whether it is implicated in HCMV response and its ability to generate adaptive response has not been shown before. In this study, we combined flow cytometry and immunosequencing of the TCR γ-chain (TRG) to analyze in-depth bone marrow (BM) graft γδ T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed for the first time that frequency of CD8+γδ T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8+γδ T cells from CMV+ grafts were mostly Vγ9- and preferentially displayed Terminal effector memory phenotype (CD27low/-CD45RO-). Furthermore, CD8+γδ T cells displayed higher proliferation and activation in response to stimuli specific for adaptive immune cells. In line with these findings, TRG immunosequencing revealed clonal focusing and reduced usage of the Vγ9/JP gene segment in γδ T cells in a CMV+ graft. We conclude that γδ T cells in BM grafts are reshaped by donor CMV serostatus and highlight potential role of CD8+γδ T cells in HCMV immune response.","prettyUrl":"gaballa-2019-sci","following":false,"created":"11/21/2019","featured":false,"publishedDate":"11/21/2019","urlOrId":"gaballa-2019-sci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"646d9f32-9088-46f0-8d8e-89653c676926","title":"Endogenous CD4+ T cells recognize neoantigens in lung cancer patients, including recurrent oncogenic KRAS and ERBB2 (Her2) driver mutations.","investigator":"Veatch, Joshua R","investigatorInstitution":"Immunotherapy Integrated Research Center, Clinical Research Division, Fred Hutchinson Cancer Research Center","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"132":"veatch-2019-cir"},"prettyUrlList":["veatch-2019-cir"],"summary":"T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8+ T cells by class I MHC. However, CD4+ class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8+ or CD4+ T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non–small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4+ T cells that recognized the recurrent KRASG12V and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. Two different T-cell receptors (TCR) specific for KRASG12V and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD–specific TCR in the tumor but not nonadjacent lung. Our results showed that CD4+ T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4+ neoantigen-specific T cells and elucidate their role in human antitumor immunity.","prettyUrl":"veatch-2019-cir","following":false,"created":"11/17/2019","featured":false,"publishedDate":"11/21/2019","urlOrId":"veatch-2019-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"41a79925-bba2-43cd-a061-489d09e4c5ca","title":"Lack of specific T- and B-cell clonal expansions in multiple sclerosis patients with progressive multifocal leukoencephalopathy","investigator":"Bertoli, Diego","investigatorInstitution":"Centro di Ricerca Emato-oncologica AIL (CREA), Diagnostic Department, ASST Spedali Civili","publicationName":"Scientific Reports","researchArea":"MS","prettyUrls":{"131":"bertoli-2019-sr"},"prettyUrlList":["bertoli-2019-sr"],"summary":"Progressive multifocal leukoencephalopathy (PML) is a rare, potentially devastating myelin-degrading disease caused by the JC virus. PML occurs preferentially in patients with compromised immune system, but has been also observed in multiple sclerosis (MS) patients treated with disease-modifying drugs. We characterized T and B cells in 5 MS patients that developed PML, 4 during natalizumab therapy and one after alemtuzumab treatment, and in treated patients who did not develop the disease. Results revealed that: i) thymic and bone marrow output was impaired in 4 out 5 patients at the time of PML development; ii) T-cell repertoire was restricted; iii) clonally expanded T cells were present in all patients. However, common usage or pairings of T-cell receptor beta variable or joining genes, specific clonotypes or obvious \"public\" T-cell response were not detected at the moment of PML onset. Similarly, common restrictions were not found in the immunoglobulin heavy chain repertoire. The data indicate that no JCV-related specific T- and B-cell expansions were mounted at the time of PML. The current results enhance our understanding of JC virus infection and PML, and should be taken into account when choosing targeted therapies.","prettyUrl":"bertoli-2019-sr","following":false,"created":"11/21/2019","featured":false,"publishedDate":"11/21/2019","urlOrId":"bertoli-2019-sr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6070a7f4-3756-4a0c-b019-ecb3604bb6e6","title":"Combined Immunodeficiency due to a loss of function mutation in DNA Polymerase Delta 1","investigator":"Cui, Ye","investigatorInstitution":"Division of Immunology, The Boston Children's Hospital. Department of Pediatrics","publicationName":"Journal of Allergy and Clinical Immunology","researchArea":"Immunocompetence","prettyUrls":{"130":"cui-2019-jaci"},"prettyUrlList":["cui-2019-jaci"],"summary":"Background: Mutations affecting DNA polymerases have been implicated in genomic instability, and cancer development, but mechanisms by which they impact the immune system remain largely unexplored.\n\nObjective: To establish the role of POLD1, encoding the DNA polymerase d 1 catalytic subunit, as the cause of a primary immunodeficiency in an extended kindred.\n\nMethods: We performed whole-exome and targeted gene sequencing, lymphocyte characterization, molecular and functional analyses of the DNA polymerase delta (Pold) complex, and T and B cell antigen receptor repertoire analysis \n\nResults: We identified a missense mutation (c. 3178C>T; p.R1060C) in POLD1 in three related subjects who presented with T cell lymphopenia and recurrent infections. The mutation disrupted the stability of the Pold complex, leading to impaired DNA replication. Molecular Dynamics simulation revealed that the R1060C mutation disrupts the intramolecular interaction between the POLD1 CysB motif and catalytic domain, and also between POLD1 and the DNA polymerase d subunit POLD2. POLD1R1060C failed to recruit replication factor C (RFC), which loads Proliferating Cell Nuclear Antigen (PCNA) onto DNA to initiate DNA replication. Vβ and Jβ usage was selectively restricted in T cells while B cells remained unaffected, suggesting a defect in VDJ recombination that was most pronounced in T cells.\n\nConclusion. These results identify gene defects in POLD1 as a novel cause of T cell immunodeficiency.","prettyUrl":"cui-2019-jaci","following":false,"created":"11/08/2019","featured":false,"publishedDate":"11/08/2019","urlOrId":"cui-2019-jaci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"017e819d-193c-46cc-b7e7-150dca83bf37","title":"Effector TH17 cells give rise to long-lived Trm cells that are essential for an immediate response against bacterial infection","investigator":"Amezcua Vesely, Maria Carolina","investigatorInstitution":"Department of Immunobiology, School of Medicine","publicationName":"Cell","researchArea":"Basic Immunology","prettyUrls":{"129":"amezcuavesely-2019-cell"},"prettyUrlList":["amezcuavesely-2019-cell"],"summary":"Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.","prettyUrl":"amezcuavesely-2019-cell","following":false,"created":"11/08/2019","featured":false,"publishedDate":"11/08/2019","urlOrId":"amezcuavesely-2019-cell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"73087661-9739-4bb4-ba66-f1235e8987e2","title":"Clonal and Constricted T cell repertoire in Common Variable Immune Deficiency","investigator":"Ramesh, Manish","investigatorInstitution":"Allergy and Immunology, Montefiore Medical Center","publicationName":"Clinical Immunology","researchArea":"Immunocompetence","prettyUrls":{"128":"ramesh-2015-ci"},"prettyUrlList":["ramesh-2015-ci"],"summary":"We used high throughput sequencing to examine the structure and composition of the β chain of the T cell receptor in Common Variable Immune Deficiency (CVID). TCRβ CDR3 regions were amplified and sequenced from genomic DNA of 44 adult CVID subjects and 22 healthy adults, using a high-throughput multiplex PCR. CVID TCRs were more similar to germline, had significantly less junctional diversity, fewer n-nucleotide insertions and deletions, and completely lacked a population of highly modified TCRs seen in healthy controls. The CVID CDR3 sequences were significantly more clonal than control DNA, and displayed unique V gene usage. Despite fewer changes from germline, increased clonality and similar infectious exposures, DNA of CVID subjects shared fewer TCR sequences as compared to controls. These abnormalities are pervasive, found in out-of-frame sequences and thus independent of selection and were not associated with specific clinical complications. These data support an inherent T cell defect in CVID.","prettyUrl":"ramesh-2015-ci","following":false,"created":"11/10/2015","featured":false,"publishedDate":"11/07/2019","urlOrId":"ramesh-2015-ci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"aea33aba-8065-425f-a304-ce696edcf826","title":"Polyfunctional, Proinflammatory, Tissue-Resident Memory Phenotype and Function of Synovial Interleukin-17A+CD8+ T Cells in Psoriatic Arthritis","investigator":"Steel, Kathryn JA","investigatorInstitution":"Centre for Inflammation Biology and Cancer Immunology (CIBCI), Department of Inflammation Biology, School of Immunology & Microbial Sciences","publicationName":"Arthritis and Rheumatology","researchArea":"Autoimmune Disorders","prettyUrls":{"127":"steel-2019-ar"},"prettyUrlList":["steel-2019-ar"],"summary":"Objective: Genetic associations imply a role for CD8+ T cells and the IL-23/IL-17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL-17A+CD8+ (Tc17) T cells are enriched in the synovial fluid of patients with PsA and IL-17A blockade is clinically efficacious in PsA/SpA. Our aim was to determine the immunophenotype, molecular profile and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis.\n\nMethods: Peripheral blood (PB) and synovial fluid (SF) mononuclear cells were isolated from patients with PsA/SpA. Cells were phenotypically, transcriptionally and functionally analysed by flow cytometry, TCRβ sequencing, RNA-seq, RT-qPCR and Luminex/ELISA.\n\nResults: IL-17A+CD8+TCRαβ+ T cells were increased in the SF vs. PB of patients with established PsA or other SpA. TCRβ sequencing showed these cells are polyclonal in PsA, whilst RNA-seq and deep-immunophenotyping revealed that PsA synovial Tc17 cells have hallmarks of Th17 (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue-resident memory T cell signature and secreted a range of pro-inflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 levels in PsA SF, which may contribute to their retention in the joint.\n\nConclusion: Our results identify synovial Tc17 cells as a polyclonal subset of tissue-resident memory T cells characterised by polyfunctional, pro-inflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other SpA.","prettyUrl":"steel-2019-ar","following":false,"created":"11/07/2019","featured":false,"publishedDate":"11/07/2019","urlOrId":"steel-2019-ar","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"03a3cbee-de3b-4ebd-b11e-a06b01c8b673","title":"Deletion of donor-reactive T cell clones following human liver transplantation","investigator":"Sykes, Megan","investigatorInstitution":"Columbia University Medical Center, Columbia University","publicationName":"American Journal of Transplantation","researchArea":"Organ transplant","prettyUrls":{"126":"savage-2019-ajt"},"prettyUrlList":["savage-2019-ajt"],"summary":"We recently developed a high throughput T cell receptor Beta chain (TCRB) sequencing-based approach to identifying and tracking donor-reactive T cells.  To address the role of clonal deletion in liver allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was achieved within 2 years of liver transplantation in 10 of 77 subjects. We identified donor-reactive T cell clones via TCRB sequencing following a pre-transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non-tolerant subjects. All subjects showed a downward trend and significant reductions in donor-reactive TCRB sequences were detected post-transplant in 6 of 8 subjects, including 2 tolerant and 4 non-tolerant recipients. Reductions in donor-reactive TCRB sequences were more pronounced than those of all other TCRB sequences, including 3rd party-reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Our results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation in humans and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ- and/or protocol-specific nature of tolerance mechanisms in humans.","prettyUrl":"savage-2019-ajt","following":false,"created":"10/04/2019","featured":false,"publishedDate":"10/07/2019","urlOrId":"savage-2019-ajt","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1ec6270f-023e-4c09-9437-02e824ce8049","title":"Human CD4+ T cells specific for Merkel cell polyomavirus localize to Merkel cell carcinomas and target a required oncogenic domain","investigator":"Koelle, David M.","investigatorInstitution":"Department of Pathology, University of Washington","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"125":"longino-2019-cir"},"prettyUrlList":["longino-2019-cir"],"summary":"Although CD4+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228–HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells, but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide a broader insight into cancer-specific CD4+ T-cell responses.","prettyUrl":"longino-2019-cir","following":false,"created":"09/25/2019","featured":false,"publishedDate":"09/25/2019","urlOrId":"longino-2019-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a9bf88a5-c23a-4091-8932-385b96460513","title":"T-cell repertoire dynamics during pregnancy in multiple sclerosis","investigator":"Gold, Stefan M","investigatorInstitution":"Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Center for Molecular Neurobiology Hamburg,","publicationName":"Cell Reports","researchArea":"MS","prettyUrls":{"124":"gold-2019-cr"},"prettyUrlList":["gold-2019-cr"],"summary":"Identifying T-cell clones associated with autoimmunity has remained challenging. Intriguingly, many human autoimmune diseases including multiple sclerosis (MS) show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease in individual patients. Here, we characterized immunomodulation at the single clone level by sequencing the T-cell receptor (TCR) repertoire in healthy women and female MS patients longitudinally over the course of pregnancy. Clonality was significantly reduced from the first to the third trimester of pregnancy in MS patients, indicating that the T-cell repertoire during MS pregnancy becomes less dominated by expanded clones. Only few T-cell clones were substantially modulated during pregnancy. In a proof-of-concept approach, we demonstrate that relapse-associated T-cell clones identified in an individual patient contracted during pregnancy and expanded during a postpartum relapse. Our data provide evidence that profiling the T-cell repertoire during pregnancy could serve as a tool to discover and track “private” T-cell clones that are associated with disease activity in individual patients.","prettyUrl":"gold-2019-cr","following":false,"created":"08/21/2019","featured":false,"publishedDate":"09/25/2019","urlOrId":"gold-2019-cr","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b6f97ee9-707f-46c7-a69c-d91ae9b7d217","title":"The combined effect of FGFR inhibition and PD-1 blockade promote tumor-intrinsic induction of antitumor immunity","investigator":"Lorenzi, Matthew V.","investigatorInstitution":"Janssen, Pharmaceutical Companies of Johnson and Johnson","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"123":"palakurthi-2019-cir"},"prettyUrlList":["palakurthi-2019-cir"],"summary":"The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients.  We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2K660N/p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti–PD-1 alone was ineffective, the erdafitinib and anti–PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C mutant genetically engineered mouse model  (GEMM), which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased TCR clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti–PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti–PD-1 drives expansion of T-cell clones and immunological changes in the tumor microenvironment to support enhanced antitumor immunity and survival.","prettyUrl":"palakurthi-2019-cir","following":false,"created":"08/20/2019","featured":false,"publishedDate":"08/20/2019","urlOrId":"palakurthi-2019-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5cf8b995-89f2-4dec-adf7-31f4db6198df","title":"T cell repertoire remodelling following post-transplant T cell therapy coincides with clinical response","investigator":"Smith Corey","investigatorInstitution":"QIMR Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute","publicationName":"Journal of Clinical Investigation","researchArea":"Organ transplant","prettyUrls":{"122":"smith-2019-jci"},"prettyUrlList":["smith-2019-jci"],"summary":"BACKGROUND. Impaired T-cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T-cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.\n\nMETHODS. In the present study, we employed high-throughput T-cell receptor Vb sequencing and T-cell functional profiling to delineate the impact of ACT on T-cell repertoire remodeling in the context of pre-therapy immunity and ACT products.\n\nRESULTS. These analyses indicated that a clinical response was coincident with significant changes in the T-cell receptor V landscape post-therapy. This restructuring was associated with the emergence of effector memory (EM) T cells in responding patients, while non-responders displayed dramatic pre-therapy T-cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products.\n\nCONCLUSION. These observations demonstrate that immune control following ACT requires significant repertoire remodeling, which may be impaired in non-responders due to the pre-existing immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.","prettyUrl":"smith-2019-jci","following":false,"created":"08/16/2019","featured":false,"publishedDate":"08/16/2019","urlOrId":"smith-2019-jci","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f13bc43f-25ad-497f-b667-7671a1c015c8","title":"Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small cell lung cancer","investigator":"Kudo, Yujin","investigatorInstitution":"Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center","publicationName":"Annals of Oncology","researchArea":"Cancer","prettyUrls":{"120":"kudo-2019-ao"},"prettyUrlList":["kudo-2019-ao"],"summary":"Background:\nThe tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We performed immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small cell lung carcinoma (NSCLC).\n\nPatients and methods:\nTIME profiling of archival formalin-fixed and paraffin embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was performed using a 770 immune gene expression panel and by T cell receptor beta repertoire (TCRß) sequencing. Immunohistochemistry was performed for validation. Targeted sequencing was performed to catalog hot spot mutations in cancer genes.\n\nResults:\nSomatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared to primary tumors (p < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared to primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (p < 0.001). T cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Further, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T cell densities were sparse in the metastases.\n\nConclusion:\nWe present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.","prettyUrl":"kudo-2019-ao","following":false,"created":"08/07/2019","featured":false,"publishedDate":"08/08/2019","urlOrId":"kudo-2019-ao","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"95e7af94-d93c-47f1-8bc4-dd04af3d9a9e","title":"Efficient tumor clearance and diversified immunity through neoepitope vaccines and combinatorial immunotherapy","investigator":"Hamilton, Duane","investigatorInstitution":"Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"121":"lee-2019-cir"},"prettyUrlList":["lee-2019-cir"],"summary":"Progressive tumor growth is associated with deficits in the immunity generated against tumor antigens. Vaccines targeting tumor neoepitopes have the potential to address qualitative defects; however, additional mechanisms of immune failure may underlie tumor progression. In such cases, patients would benefit from additional immune-oncology agents targeting potential mechanisms of immune failure. The present study explores the identification of neoepitopes in the MC38 colon carcinoma model by comparison of tumor to normal DNA  and tumor RNA sequencing technology, as well as neoepitope delivery by both peptide- and adenovirus-based vaccination strategies. To improve antitumor efficacies, we combined the vaccine with a group of rationally selected immune-oncology agents. We utilized an IL15 superagonist to enhance the development of antigen-specific immunity initiated by the neoepitope vaccine, PD-L1 blockade to reduce tumor immunosuppression, and a tumor-targeted IL12 molecule to facilitate T cell function within the tumor microenvironment. Analysis of tumor-infiltrating leukocytes demonstrated this multifaceted treatment regimen was required to promote the influx of CD8+ T cells and enhance the expression of transcripts relating to T-cell activation/effector function. Tumor-targeted IL12 resulted in a marked increase in clonality of T cell repertoire infiltrating the tumor, which when sculpted with the addition of either a peptide or adenoviral neoepitope vaccine promoted efficient tumor clearance. Additionally, the neoepitope vaccine induced the spread of immunity to neoepitopes expressed by the tumor but not contained within the vaccine. These results demonstrate the importance of combining neoepitope-targeting vaccines with a multifaceted treatment regimen to generate effective antitumor immunity.","prettyUrl":"lee-2019-cir","following":false,"created":"06/19/2019","featured":false,"publishedDate":"08/08/2019","urlOrId":"lee-2019-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2df7adb7-09ac-46fc-a0cd-f8ae7397ba49","title":"T cell clonal expansions in ileal Crohn’s disease are associated with smoking behaviour and postoperative recurrence","investigator":"Allez, Matthieu","investigatorInstitution":"Gastroenterology, Hopital Saint Louis","publicationName":"Gut","researchArea":"Gastrointestinal","prettyUrls":{"119":"allez-2019-gut"},"prettyUrlList":["allez-2019-gut"],"summary":"T cell clonal expansions are present in the inflamed mucosa of patients with Crohn’s disease (CD) and may be implicated in postoperative recurrence after ileocolonic resection.\n\nMethods:\nT cell receptor (TCR) analysis was performed in 57 patients included in a prospective multicentre cohort. Endoscopic recurrence was defined by a Rutgeerts score >i0. DNA and mRNA were extracted from biopsies collected from the surgical specimen and endoscopy, and analysed by high throughput sequencing and microarray, respectively.\n\nResults:\nTCR repertoire in the mucosa of patients with CD displayed diverse clonal expansions. Active smokers at time of surgery had a significantly increased proportion of clonal expansions as compared with non-smokers (25.9%vs17.9%, p=0.02). The percentage of high frequency clones in the surgical specimen was significantly higher in patients with recurrence and correlated with postoperative endoscopic recurrence (area under the curve (AUC) 0.69, 95% CI 0.54 to 0.83). All patients with clonality above 26.8% (18/57) had an endoscopic recurrence. These patients with a high clonality were more frequently smokers than patients with a low clonality (61% vs 23%, p=0.005). The persistence of a similar TCR repertoire at postoperative endoscopy was associated with smoking and disease recurrence. Patients with high clonality showed increased expression of genes associated with CD8 T cells and reduced expression of inflammation-related genes. Expanded clones were found predominantly in the CD8 T cell compartment.\n\nConclusion:\nClonal T cell expansions are implicated in postoperative endoscopic recurrence. CD patients with increased proportion of clonal T cell expansions in the ileal mucosa represent a subgroup associated with smoking and where pathogenesis appears as T cell driven.\n\nTRIAL REGISTRATION NUMBER: NCT03458195","prettyUrl":"allez-2019-gut","following":false,"created":"08/05/2019","featured":false,"publishedDate":"08/05/2019","urlOrId":"allez-2019-gut","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"dcb28451-cadb-4df2-bedc-a94a5e1729c9","title":"Clonal replacement of tumor-specific T cells following PD-1 blockade","investigator":"Chang,  Howard","investigatorInstitution":"Stanford University School of Medicine","publicationName":"Nature Medicine","researchArea":"Cancer Immunotherapy","prettyUrls":{"115":"yost-2019-natmed"},"prettyUrlList":["yost-2019-natmed"],"summary":"Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor infiltrating T cells (TILs) or on recruitment of novel T cells remains unclear. Here, we performed paired single-cell RNA (scRNA) and T cell receptor (TCR)- sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction marked by clonal expansions of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing TIL clones; rather, it was comprised of novel clonotypes not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in BCC and SCC patients. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.","prettyUrl":"yost-2019-natmed","following":false,"created":"05/20/2019","featured":false,"publishedDate":"07/29/2019","urlOrId":"yost-2019-natmed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"8a16b5c7-2bef-4829-8743-7e9ed3fe18d2","title":"Siplizumab selectively depletes effector memory T-cells and promotes a relative expansion of alloreactive regulatory T-cells in vitro","investigator":"Sykes, Megan","investigatorInstitution":"Columbia Center for Translational Immunology, Department of Medicine","publicationName":"American Journal of Transplantation","researchArea":"Response to Therapeutic Agent","prettyUrls":{"114":"podesta-2019-ajt"},"prettyUrlList":["podesta-2019-ajt"],"summary":"Siplizumab, a humanized anti-CD2 monoclonal antibody, has been used in conditioning regimens for hematopoietic cell transplantation and tolerance induction with combined kidney-bone marrow transplantation. Siplizumab-based tolerance induction regimens deplete T cells globally while enriching regulatory T cells (Tregs) early post-transplantation. Siplizumab inhibits allogeneic mixed-lymphocyte reactions (MLRs) in vitro. We compared the impact of siplizumab on Tregs versus other T-cell subsets in HLA-mismatched allogeneic MLRs using PBMCs. Siplizumab predominantly reduced the percentage of CD4+ and CD8+ effector memory T cells, which express higher CD2 levels than naïve T cells or resting Tregs. Conversely, siplizumab enriched proliferating CD45RA- FoxP3HI cells in MLRs. FoxP3 expression was stable over time in siplizumab-containing cultures, consistent with enrichment for bona fide Tregs. Consistently, high-throughput TCRβ CDR3 sequencing of sorted unstimulated and proliferating T cells in MLRs revealed selective expansion of donor-reactive Tregs along with depletion of donor-reactive CD4+ effector/memory T cells in siplizumab-containing MLRs. These results indicate that siplizumab may have immunomodulatory functions that may contribute to its success in tolerance-inducing regimens. Our studies also confirm that naïve in addition to effector/memory T cells contribute to the allogeneic MLR and mandate further investigation of the impact of siplizumab on alloreactive naïve T cells.","prettyUrl":"podesta-2019-ajt","following":false,"created":"07/22/2019","featured":false,"publishedDate":"07/23/2019","urlOrId":"podesta-2019-ajt","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ec4db843-1e59-4296-82af-53e0e935a005","title":"Human urothelial bladder cancer generates a clonal immune response: The results of T-cell receptor sequencing","investigator":"Sankin, Alexander","investigatorInstitution":"Department of Urology, Montefiore Medical Center and Albert Einstein College of Medicine","publicationName":"Urologic Oncology","researchArea":"Cancer","prettyUrls":{"113":"sankin-2019-uroloncol"},"prettyUrlList":["sankin-2019-uroloncol"],"summary":"Background: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer.\n\nObjective: To determine if TCR repertoire is more clonal in tumors than in benign inflammation.\n\nMethods: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at -80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum\nfrequency of TCR clone were assessed.\n\nResults: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC-) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC- specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC- specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17% of the total tumor infiltrating lymphocyte pool, in contrast to 2% among UC- specimens.\n\nConclusions: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance. \u0001","prettyUrl":"sankin-2019-uroloncol","following":false,"created":"07/19/2019","featured":false,"publishedDate":"07/21/2019","urlOrId":"sankin-2019-uroloncol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"76d27b29-1c32-4506-b731-13b1174b0332","title":"AIRE expression controls the peripheral selection of autoreactive B cells","investigator":"Meffre, Eric","investigatorInstitution":"Department of Immunobiology","publicationName":"Science Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"112":"sng-2019-sciimmunol"},"prettyUrlList":["sng-2019-sciimmunol"],"summary":"Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue- specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in increased proportions of autoreactive clones in their mature naïve B cell compartment. Proteomic arrays and Biacore affinity measurements revealed that many unmutated antibodies expressed by naïve B cells from AIRE-deficient patients recognized soluble molecules and cytokines including insulin, IL-17A and IL-17F, and endocrine-associated molecules, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. In addition, APECED patients displayed decreased frequencies of regulatory T cells that lacked common TCR clonotypes, some of which were found instead in their conventional T cell compartment. Hence, AIRE-mediated T cell selection normally prevents the accumulation of autoreactive naïve B cells recognizing peripheral self-antigens.","prettyUrl":"sng-2019-sciimmunol","following":false,"created":"04/30/2018","featured":false,"publishedDate":"07/03/2019","urlOrId":"sng-2019-sciimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"64035a30-76ca-4ec9-9f00-34b5963f2c1a","title":"Strong selection of a few dominant CD8 clones in a TLR7-dependent autoimmune mouse model","investigator":"Morawski, Peter A","investigatorInstitution":"Laboratory of Immunogenetics","publicationName":"ImmunoHorizons","researchArea":"Autoimmune Disorders","prettyUrls":{"111":"morawski-2019-ih"},"prettyUrlList":["morawski-2019-ih"],"summary":"Systemic lupus disease is characterized by the expansion of a self-reactive repertoire of B cells that, with the help of CD4 cells, generate IgG antibodies against common nuclear antigens. Meanwhile, the functional state and posible clonal selection of CD8 cells in lupus remain poorly defined. We previously described the activated but non-pathogenic phenotype of CD8+ T cells, some of which accumulate in the brain, in a model of systemic autoimmune disease triggered by increased copy number of the tlr7 gene (TLR7tg mice). Here we report, through the analysis of TCRb sequences, that CD8+ cells from TLR7tg are strongly selected for a small number of clones, some of them reaching 30% of the repertoire, compared to less than 0.4% for a single top clone in wild type cells. High frequency clones are variable in sequence among individual TLR7tg mice and are distinct from top clones in WT, while cells from spleen and brain-resident cells from the same animals have perfect concordance. These results suggest that top CD8 clones are selected in stochastic fashion in each animal but limit further diversification, and that brain infiltrating CD8 cells in TLR7tg are not selected by a tissue specific antigen. This kind of extreme clonal dominance and narrowing of the CD8+ T cell repertoire could potentially impair anti-viral responses and should be considered as an additional detrimental feature of chronic autoimmune disease.","prettyUrl":"morawski-2019-ih","following":false,"created":"06/04/2019","featured":false,"publishedDate":"06/04/2019","urlOrId":"morawski-2019-ih","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5831b417-31a6-489d-aa23-eaad49084e27","title":"A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen","investigator":"Rizwan Ahmed","investigatorInstitution":"Department of Pathology, Johns Hopkins University School of Medicine","publicationName":"Cell","researchArea":"T1D","prettyUrls":{"110":"ahmed-2019-cell"},"prettyUrlList":["ahmed-2019-cell"],"summary":"T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.","prettyUrl":"ahmed-2019-cell","following":false,"created":"06/03/2019","featured":false,"publishedDate":"06/04/2019","urlOrId":"ahmed-2019-cell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f851c65c-24cb-4153-b1e0-37e20d15ee90","title":"Comprehensive characterization of a next-generation antiviral T-cell product and feasibility for application in immunosuppressed transplant patients","investigator":"Schmueck-Henneresse, Michael","investigatorInstitution":"Charité University Medicine","publicationName":"Frontiers in Immunology","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"109":"amini-2019-frontimmunol"},"prettyUrlList":["amini-2019-frontimmunol"],"summary":"Viral infections have a major impact on morbidity and mortality of immunosuppressed solid organ transplant (SOT) patients because of missing or failure of adequate pharmacologic antiviral treatment. Adoptive antiviral T-cell therapy (AVTT), regenerating disturbed endogenous T-cell immunity, emerged as an attractive alternative approach to combat severe viral complications in immunocompromised patients. AVTT is successful in patients after hematopoietic stem cell transplantation where T-cell products (TCPs) are manufactured from healthy donors. In contrast, in the SOT setting TCPs are derived from/applied back to immunosuppressed patients. We and others demonstrated feasibility of TCP generation from SOT patients and first clinical proof-of-concept trials revealing promising data. However, the initial efficacy is frequently lost long-term, because of limited survival of transferred short-lived T-cells indicating a need for next-generation TCPs. Our recent data suggest that Rapamycin treatment during TCP manufacture, conferring partial inhibition of mTOR, might improve its composition. The aim of this study was to confirm these promising observations in a setting closer to clinical challenges and to deeply characterize the next-generation TCPs.\nUsing cytomegalovirus (CMV) as model, our next-generation Rapamycin-treated (Rapa-)TCP showed consistently increased proportions of CD4+ T-cells as well as CD4+ and CD8+ central-memory T-cells (TCM). In addition, Rapamycin sustained T-cell function despite withdrawal of Rapamycin and re-stimulation, showed superior T-cell viability and resistance to apoptosis, stable metabolism upon activation, preferential expansion of TCM, partial conversion of other memory T-cell subsets to TCM and increased clonal diversity. On transcriptome level, we observed a gene expression profile denoting long-lived early memory T-cells with potent effector functions. Furthermore, we successfully applied the novel protocol for the generation of Rapa-TCPs to 19/19 SOT patients in a comparative study, irrespective of their history of CMV reactivation. Moreover, comparison of paired TCPs generated before/after transplantation did not reveal inferiority of the latter despite exposition to maintenance immunosuppression post-SOT. Our data imply that the Rapa-TCPs, exhibiting longevity and sustained T-cell memory, are a reasonable treatment option for SOT patients. Based on our success to manufacture Rapa-TCPs from SOT patients under maintenance immunosuppression, now, we seek ultimate clinical proof of efficacy in a clinical study.","prettyUrl":"amini-2019-frontimmunol","following":false,"created":"05/16/2019","featured":false,"publishedDate":"05/16/2019","urlOrId":"amini-2019-frontimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"cd93a391-829b-4cb0-b015-65c8240da116","title":"Rational design of anti-GITR-based combination immunotherapy.","investigator":"Merghoub, Taha","investigatorInstitution":"Memorial Sloan Kettering Cancer Center","publicationName":"Nature Medicine","researchArea":"Response to Therapeutic Agent","prettyUrls":{"107":"zappasodi-2019-natmed"},"prettyUrlList":["zappasodi-2019-natmed"],"summary":"Modulating T-cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T-cell responses. However, many patients still do not benefit from checkpoint blockade, highlighting the need of targeting alternative immune pathways. Glucocorticoid-induced TNFR-related protein (GITR) is an attractive target for immunotherapy, due to its capacity to promote effector T-cell (Teff) functions and hamper regulatory T-cell (Treg) suppression. Based on the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others, we initiated the first in-human phase-I trial of GITR agonism with the anti-GITR antibody TRX518 (NCT01239134). Here, we report the safety profile and immune effects of TRX518 monotherapy in advanced cancer patients and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral Tregs to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite Treg reductions and increased Teff:Treg ratios, substantial\nclinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic CD8+ T cells due to persistent exhaustion. We demonstrate that T-cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors (NCT02628574).","prettyUrl":"zappasodi-2019-natmed","following":false,"created":"04/30/2019","featured":false,"publishedDate":"04/30/2019","urlOrId":"zappasodi-2019-natmed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"280f3bf3-e250-4dd1-8ecc-5b6d10a77954","title":"Negative Co-stimulation Constrains T Cell Differentiation by Imposing Boundaries on Possible Cell States","investigator":"Wei, Spencer","investigatorInstitution":"The University of Texas MD Anderson Cancer Center","publicationName":"Immunity","researchArea":"Basic Immunology","prettyUrls":{"108":"wei-2019-immunity"},"prettyUrlList":["wei-2019-immunity"],"summary":"Co-stimulation regulates T cell activation, but it remains unclear whether co-stimulatory pathways also control T cell differentiation. We used mass cytometry to profile T cells generated in the genetic absence of the negative co-stimulatory molecules CTLA-4 and PD-1. Our data indicate that negative co-stimulation constrains the possible cell states that peripheral T cells can acquire. CTLA-4 imposes major boundaries on CD4+ T cell phenotypes, whereas PD-1 subtly limits CD8+ T cell phenotypes. By computationally reconstructing T cell differentiation paths, we identified protein expression changes that underlied the abnormal phenotypic expansion and pinpointed when lineage choice events occurred during differentiation. Similar alterations in T cell phenotypes were observed after anti-CTLA-4 and anti-PD-1 antibody blockade. These findings implicate negative co-stimulation as a key regulator and determinant of T cell differentiation and suggest that checkpoint blockade might work in part by altering the limits of T cell phenotypes.","prettyUrl":"wei-2019-immunity","following":false,"created":"03/27/2019","featured":false,"publishedDate":"04/30/2019","urlOrId":"wei-2019-immunity","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"825f8d70-ee69-4864-83ab-42e93f4955a3","title":"Siglec-9 is a regulator of an effector memory CD8+ T cell subset that congregates in the melanoma tumor microenvironment","investigator":"Haas, Quentin","investigatorInstitution":"Institute of Pharmacology, University of Bern","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"106":"haas-2019-cir"},"prettyUrlList":["haas-2019-cir"],"summary":"Emerging evidence suggests an immunosuppressive potential of altered tumor glycosylation by downregulating innate immune responses via immunoregulatory Siglecs. In contrast, human T cells, major anti-cancer effector cells, only rarely express Siglecs. However, here we report that the majority of intratumoral, but not peripheral blood, cytotoxic CD8+ T cells expressed Siglec-9 in melanoma. We identified Siglec-9+ CD8+ T cells as a subset of effector memory cells with high functional capacity and signatures of clonal expansion. This cytotoxic T cell subset was functionally inhibited in the presence of cognate ligands or by Siglec-9 engagement by specific antibodies. TCR signaling pathways and key effector functions (cytotoxicity, cytokine production) of CD8+ T cells were suppressed by Siglec-9 engagement, which was associated with the phosphorylation of inhibitory SHP-1, but not SHP-2. Notably, expression of cognate Siglec-9 ligands was observed on the majority of tumor cells in primary and metastatic melanoma specimens. Targeting the tumor restricted glycosylation-dependent Siglec-9 axis may unleash this major subset of intratumoral T cells, yet confine T cell activation to the tumor microenvironment.","prettyUrl":"haas-2019-cir","following":false,"created":"03/25/2019","featured":false,"publishedDate":"03/26/2019","urlOrId":"haas-2019-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"098e585f-6543-4e6d-9542-abf2cf0a553e","title":"Mobilization of CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer","investigator":"Seo, Yongwoo David","investigatorInstitution":"Department of Surgery","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"105":"seo-2019-clincancerres"},"prettyUrlList":["seo-2019-clincancerres"],"summary":"The value of endogenous CD8+ T cells re-activated by checkpoint-directed cancer immunotherapy depends on their appropriate location within the cancer. In human pancreatic ductal adenocarcinoma (PDA), CD8+ T cells were often present, but we found them localized to the stroma, and not immediately adjacent to cancer cells. However, T cells within PDA tumors showed evidence of antigen-driven repertoire selection, suggesting they might have anti-cancer potential. By inhibiting the CXCR4 chemokine receptor, we found these cells were able to migrate from the stroma into cancer cell-rich regions, and that PD-1 blockade was then able to activate cancer cell killing. These outcomes were consistent across a large number of individual patients’ cancers. These results provide a new basis for the rational selection of combination immunotherapy for PDA, a disease for which traditional therapy is relatively ineffective.","prettyUrl":"seo-2019-clincancerres","following":false,"created":"03/17/2019","featured":false,"publishedDate":"03/18/2019","urlOrId":"seo-2019-clincancerres","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f7ac0410-217a-4de4-b492-e69d926c6f21","title":"Altered T Cell Receptor Beta Repertoire Patterns in Pediatric Ulcerative Colitis","investigator":"Shouval, Dror S.","investigatorInstitution":"Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center","publicationName":"Clinical and Experimental Immunology","researchArea":"Gastrointestinal","prettyUrls":{"104":"werner-2018-clinexpimmunol"},"prettyUrlList":["werner-2018-clinexpimmunol"],"summary":"Background: The antigenic specificity of T cells occurs via generation and rearrangement of different gene segments producing a functional T cell receptor (TCR). High throughput sequencing (HTS) allows in-depth assessment of TCR repertoire patterns. There is limited data whether TCR repertoires are altered in inflammatory bowel disease. We hypothesized that pediatric ulcerative colitis (UC) patients possess unique TCR repertoires, resulting from clonotypic expansions in the gut.\n\nMethods: Paired blood and rectal samples were collected from nine newly-diagnosed treatment-naïve pediatric UC patients and four healthy controls. DNA was isolated to determine the TCRβ repertoire by HTS.\n\nResults: Significant clonal expansion was demonstrated in UC patients, with inverse correlation between clinical disease severity and repertoire diversity in the gut. Using different repertoire variables in rectal biopsies, a clear segregation was observed between patients with severe UC, those with mild-moderate disease and healthy controls. Moreover, the overlap between autologous blood-rectal samples in UC patients was significantly higher compared with overlap among controls. Finally, we identified several clonotypes that were shared in either all or majority of UC patients in the colon.\n\nConclusions: Clonal expansion of TCRβ-expressing T cells among UC patients correlates with disease severity and highlights their involvement in mediating intestinal inflammation.","prettyUrl":"werner-2018-clinexpimmunol","following":false,"created":"03/07/2019","featured":false,"publishedDate":"03/07/2019","urlOrId":"werner-2018-clinexpimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c2bee14c-6aa9-48f6-923c-b364a7281885","title":"Subclonal STAT3 Mutations Solidify Clonal Dominance","investigator":"Maciejewski, Jaroslaw","investigatorInstitution":"Cleveland Clinic Taussig Cancer Institute","publicationName":"Blood Advances","researchArea":"Cancer","prettyUrls":{"103":"kerr-2019-bloodadvances"},"prettyUrlList":["kerr-2019-bloodadvances"],"summary":"T large granular lymphocyte leukemia (T-LGLL), a clonal lymphoproliferative disorder that can arise in the context of pathologic or physiologic cytotoxic T cell (CTLs) responses. STAT3 mutations are often absent in typical T-LGLL suggesting that in a significant fraction of patients antigen–driven expansion alone can maintain LGL clone persistence. We set here to determine the relationship between activating STAT3 hits and CTL clonal selection at presentation and in response to therapy. Thus a group of T-LGLL patients were serially subjected to deep NGS based sequencing of the T cell receptor Vβ complementarity-determining region 3 and STAT3 to recapitulate clonal hierarchy and dynamics. The results of this complex analysis demonstrate that STAT3 mutations produce either a sweeping or linear subclone within a monoclonal CTL population either early or during the course of disease. Therapy can either extinguish a LGL clone, silence it or adapt mechanisms to escape elimination. LGL clones can persist upon elimination of STAT3 subclones and alternate STAT3 negative CTL clones can replace therapy-sensitive CTL clones. LGL clones can evolve and are fuelled by a non-extinguished antigenic drive. STAT3 mutations can accelerate this process or render CTL clones semi-autonomous and not reliant upon physiologic stimulation.","prettyUrl":"kerr-2019-bloodadvances","following":false,"created":"01/31/2019","featured":false,"publishedDate":"02/12/2019","urlOrId":"kerr-2019-bloodadvances","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1950448d-1a4c-4e88-b103-f464fb1dd8c3","title":"Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire","investigator":"Sun, Peter","investigatorInstitution":"Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases","publicationName":"Nature Communications","researchArea":"Basic Immunology","prettyUrls":{"102":"lu-2019-natcomms"},"prettyUrlList":["lu-2019-natcomms"],"summary":"The αβ T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficient mouse strains, and find that MHC-restricted and MHC-independent TCRs are primarily distinguished by features in their non-germline CDR3 regions, with many pre-selection CDR3 sequences not compatible with MHC-binding. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR is restricted by both CDR3 length and specific amino acid usage. MHC-restriction disfavors TCR with CDR3 longer than 13 amino acids, limits positively charged and hydrophobic amino acids in CDR3β, and clonally deletes TCRs with cysteines in their CDR3 peptide-binding regions. Together, these MHC-imposed structural constraints form the basis to shape VDJ recombination sequences into MHC-restricted repertoires.","prettyUrl":"lu-2019-natcomms","following":false,"created":"02/05/2019","featured":false,"publishedDate":"02/05/2019","urlOrId":"lu-2019-natcomms","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6f221879-d289-4786-b9cd-1c9b5cc72be9","title":"Association of Tumor Microenvironment T-Cell Repertoire and Mutational Load With Clinical Outcome After Sequential Checkpoint Blockade in Melanoma","investigator":"Weber, Jeffrey","investigatorInstitution":"Laura and Isaac Perlmutter Cancer Center","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"100":"weber-2018-cir"},"prettyUrlList":["weber-2018-cir"],"summary":"To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by immunohistochemistry, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor -chain locus (TCR) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and post treatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T cell clonality and fraction. Mutational and neoantigen load were also assessed by NGS in 82 of the 91 patients. Tumors were stained using immunohistochemistry for PD-L1+ and CD8+ T cells. Pretreatment tumor TCR clonality and neoantigen load were marginally associated with best response with nivo/ipi (P = 0.04 and 0.05, respectively), but not with ipi/nivo. Amalgamated pretreatment mutational load and tumor T cell fraction were significantly associated with best response with nivo/ipi (P = .002). Pretreatment PD-L1 staining intensity and CD8+ T-cell counts were correlated with T-cell fraction and clonality, but not mutational or neoantigen load. Patients with increased T-cell fraction post-treatment at week 13 had a 30-fold increased likelihood of survival (P = .002). Mutational and neoantigen load, and T-cell infiltrate within the tumor, were associated with outcome of sequential checkpoint inhibition using nivolumab then ipilimumab, but not when ipilimumab was administered before nivolumab.","prettyUrl":"weber-2018-cir","following":false,"created":"01/28/2019","featured":false,"publishedDate":"01/28/2019","urlOrId":"weber-2018-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9af912e3-5090-449c-8a56-e1cc917cfa45","title":"Helios+ and Helios− Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires","investigator":"Thornton, Angela","investigatorInstitution":"NIAID/NIH","publicationName":"European Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"101":"thornton-2019-eji"},"prettyUrlList":["thornton-2019-eji"],"summary":"The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs. We previously proposed that Helios is a marker of thymic derived Treg (tTreg), while Helios− Treg were induced from Foxp3− T conventional (Tconv) cells in the periphery (pTreg). To compare the two Treg subpopulations, we generated Helios‐GFP reporter mice and crossed them to Foxp3‐RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype, had a slightly higher suppressive capacity in vitro and expressed a more highly demethylated TSDR but were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios− Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios− Treg when transferred to lymphopenic mice. Gene expression profiling demonstrated a large number of differentially expressed genes and showed that Helios− Treg expressed certain genes normally expressed in CD4+Foxp3− T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios− Treg. Thus, Helios+ and Helios− Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires.","prettyUrl":"thornton-2019-eji","following":false,"created":"07/25/2018","featured":false,"publishedDate":"01/28/2019","urlOrId":"thornton-2019-eji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"810e4b4a-c1c4-4039-ab5b-1f690af675c7","title":"Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice","investigator":"Candéias, Serge M","investigatorInstitution":"Laboratory of Chemistry and Biology of Metals","publicationName":"Cellular and Molecular Life Sciences","researchArea":"Response to Therapeutic Agent","prettyUrls":{"99":"candeias-2019-mouse"},"prettyUrlList":["candeias-2019-mouse"],"summary":"While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces \"aging-like\" effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.","prettyUrl":"candeias-2019-mouse","following":false,"created":"01/04/2019","featured":false,"publishedDate":"01/04/2019","urlOrId":"candeias-2019-mouse","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ffe7029a-e263-4ae9-9ac9-b68ced5f8a22","title":"Multifactorial Heterogeneity of Virus-specific T Cells and Association with the Progression of Human Chronic Hepatitis B Infection","investigator":"Cheng, Yang","investigatorInstitution":"Singapore Immunology Network","publicationName":"Science Immunology","researchArea":"Infectious Disease","prettyUrls":{"98":"cheng-2018-sciimmunol"},"prettyUrlList":["cheng-2018-sciimmunol"],"summary":"Associations between chronic antigen stimulation, T cell dysfunction and the expression of various inhibitory receptors are well characterized in several mouse and human systems. However, during chronic hepatitis B virus (CHB) infection T cell responses are blunted with low frequencies of virus-specific T cells observed making these parameters difficult to study. Here, using mass cytometry and a highly multiplexed combinatorial pMHC tetramer strategy that allows for the detection of rare antigen-specific T cells, we simultaneously probed 484 unique HLA-A*1101-restricted epitopes spanning the entire hepatitis B virus (HBV) genome on T cells from patients at various stages of CHB. Numerous HBV-specific T cell populations were detected, validated and profiled. T cells specific for two of epitopes (HBVpol387 and HBVcore169) displayed differing and complex heterogeneities that were associated with the disease progression, and the expression of inhibitory receptors on these cells were not linearly related with their extent of T cell dysfunction. For HBVcore169-specific CD8+ T cells, we found that cellular markers associated with long-term memory, poly-functionality, as well as the presence of several previously unidentified public TCR clones correlated with viral control. Using high-dimensional trajectory analysis of these cellular phenotypes, a pseudo-time metric was constructed that fit with the status of viral infection in corresponding patients. This was validated in a longitudinal cohort of patients undergoing anti-viral therapy. Our study uncovers complex relationships of inhibitory receptors between the profiles of antigen-specific T cells and the status of CHB with implications for new strategies of therapeutic intervention.","prettyUrl":"cheng-2018-sciimmunol","following":false,"created":"01/03/2019","featured":false,"publishedDate":"01/04/2019","urlOrId":"cheng-2018-sciimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"19acd942-2bf4-4f75-8e85-30192017c5b1","title":"Cytomegalovirus Exposure in the Elderly Does Not Reduce CD8 T cell Repertoire Diversity","investigator":"Lindau, Paul","investigatorInstitution":"Fred Hutchinson Cancer Research Center and University of Washington School of Medicinie","publicationName":"Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"97":"lindau-2018-ji"},"prettyUrlList":["lindau-2018-ji"],"summary":"With age, the immune system becomes less effective, causing increased susceptibility to infection. Chronic cytomegalovirus (CMV) infection further impairs immune function and is associated with increased mortality in the elderly.  CMV exposure elicits massive CD8+ T cell clonal expansions and diminishes the cytotoxic T cell response to subsequent infections, leading to the hypothesis that, in order to maintain homeostasis, T cell clones are expelled from the repertoire, reducing T cell repertoire diversity and diminishing the ability to combat new infections.  However, in humans, the impact of CMV infection on the structure and diversity of the underlying T cell repertoire remains uncharacterized.  Using T cell receptor β chain immunosequencing, we observed that the proportion of the peripheral blood T cell repertoire comprised of the most numerous 0.1% of clones is larger in the CMV seropositive and gradually increases with age.  We found that the T cell repertoire in the elderly grows to accommodate CMV-driven clonal expansions while preserving its underlying diversity and clonal structure.  Our observations suggest that the maintenance of large CMV-reactive T cell clones throughout life does not compromise the underlying repertoire.  Alternatively, we propose that the diminished immunity in elderly individuals with CMV is due to alterations in cellular function rather than a reduction in CD8+ T cell repertoire diversity.","prettyUrl":"lindau-2018-ji","following":false,"created":"12/13/2018","featured":false,"publishedDate":"12/13/2018","urlOrId":"lindau-2018-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e68940a8-df1a-4612-9f85-61169d5b2735","title":"Graft gd T-cell receptor sequencing identifies public clonotypes associated to hematopoietic stem cell transplantation efficacy in acute myeloid leukemia patients and unravels cytomegalovirus impact on repertoire distribution","investigator":"Arruda, Lucas","investigatorInstitution":"Karolinska Institutet","publicationName":"Journal of Immunology","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"96":"arruda-2018-jimmunology"},"prettyUrlList":["arruda-2018-jimmunology"],"summary":"Although the impact of donor graft composition on clinical outcome after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intra-graft gd T-cell receptor (TCR) repertoire on clinical outcome following HSCT. Using a high-throughput sequencing platform we sought to analyze the TCR g-chain (TRG) repertoire of gd T-cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of twenty peripheral blood stem cell grafts were analyzed and donors classified as CMV-positive/negative. The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed over-represented clones. This was more prominent in grafts from CMV-positive donors, which presented a more private repertoire, lower diversity, skewed distribution and reduced usage of V9-JP pairing. Grafts given to non-relapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-Joining gene segment usage was not associated to aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 was observed in grafts given to non-relapse patients. Our work identified five private over-represented and one public CDR3 sequence (CATWDGPYYKKLF) associated to CMV infection in addition to twelve highly frequent public sequences present exclusively in grafts given to non-relapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated to aGvHD incidence and several public sequences are associated to clinical remission.","prettyUrl":"arruda-2018-jimmunology","following":false,"created":"12/06/2018","featured":false,"publishedDate":"12/10/2018","urlOrId":"arruda-2018-jimmunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7c28a753-ee06-4e79-abf0-34209ae06100","title":"Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that are Maintained by a Circulating Pool","investigator":"Fu, Jianing","investigatorInstitution":"Columbia Center for Translational Immunology","publicationName":"Cell Stem Cell","researchArea":"Organ transplant","prettyUrls":{"94":"fu-2018-cellstemcell"},"prettyUrlList":["fu-2018-cellstemcell"],"summary":"Long-term mixed chimerism often appears in blood following human intestinal transplantation (ITx). We find that circulating donor T cells are markedly enriched for the recent thymic emigrant phenotype and T cell receptor excision circles, lack repertoire overlap with pre-ITx donor lymphocytes, and are tolerant to recipient but not third party stimulators. Consistent with the possibility that blood chimerism originated from progenitors in the graft, we detected donor-derived hematopoietic stem and progenitor cells (HSCs/HPs) in intestinal mucosa, Peyer’s patches, mesenteric lymph nodes, and liver from deceased donors. Human gut HSCs/HPs are phenotypically similar to bone marrow HSCs/HPs and have multilineage differentiation potential both in vitro and in vivo. Our longitudinal study of human HSCs/HPs carried in intestinal allografts demonstrates their turnover kinetics in the graft and their replacement from a circulating pool. Thus, we have demonstrated the existence of functioning HSCs/HPs in intestinal tissues and the circulation of human beings.","prettyUrl":"fu-2018-cellstemcell","following":false,"created":"11/20/2018","featured":false,"publishedDate":"11/29/2018","urlOrId":"fu-2018-cellstemcell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5dd64c79-8817-4d39-a2dd-ef341581fc5d","title":"Resident memory and recirculating memory T cells cooperate to maintain disease in a mouse model of vitiligo","investigator":"Richmond, Jillian","investigatorInstitution":"Department of Medicine, Division of Dermatology","publicationName":"Journal of Investigative Dermatology","researchArea":"Autoimmune Disorders","prettyUrls":{"95":"richmond-2018-jinvestdermatol"},"prettyUrlList":["richmond-2018-jinvestdermatol"],"summary":"Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFNγ, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients.","prettyUrl":"richmond-2018-jinvestdermatol","following":false,"created":"09/22/2015","featured":false,"publishedDate":"11/26/2018","urlOrId":"richmond-2018-jinvestdermatol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c1c6177a-c09f-4ab5-873e-24a6b80eeecf","title":"Early expansion of donor-specific Tregs in tolerant kidney transplant recipients","investigator":"Savage, Thomas M","investigatorInstitution":"Columbia Center for Translational Immunology, Department of Medicine","publicationName":"JCI Inshight","researchArea":"Organ transplant","prettyUrls":{"92":"savage-2018-jciinsight"},"prettyUrlList":["savage-2018-jciinsight"],"summary":"Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early post-CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT. We expanded Tregs with several different protocols. Using functional analyses and T cell receptor sequencing, we found that expanding sorted Tregs with activated donor B cells identified the broadest Treg repertoire with the greatest potency and donor specificity of suppression. This method outperformed both alloantigen stimulation with CTLA4Ig and sequencing of CFSElo cells from the primary mixed lymphocyte reaction. In 3 tolerant and 1 non-tolerant CKBMT recipients, we sequenced donor-specific Tregs pre-transplant and tracked them post-transplant. Pre-existing donor-specific Tregs were expanded at 6 months post-CKBMT in tolerant patients and were reduced in the non-tolerant patient. These results suggest that early expansion of donor-specific Tregs is involved in tolerance induction following CKBMT.","prettyUrl":"savage-2018-jciinsight","following":false,"created":"07/02/2018","featured":false,"publishedDate":"11/15/2018","urlOrId":"savage-2018-jciinsight","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2a401fa7-0865-41ad-b335-0f4e822e7db0","title":"Radiotherapy induces responses of lung cancer to CTLA-4 blockade","investigator":"Formenti, Silvia C.","investigatorInstitution":"Department of Radiation Oncology","publicationName":"Nature Medicine","researchArea":"Cancer Immunotherapy","prettyUrls":{"93":"formenti-2018-natmed"},"prettyUrlList":["formenti-2018-natmed"],"summary":"Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.","prettyUrl":"formenti-2018-natmed","following":false,"created":"03/15/2018","featured":false,"publishedDate":"11/12/2018","urlOrId":"formenti-2018-natmed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ca806f0a-6112-483b-a8e4-2e72620c33b7","title":"High prevalence of S. pyogenes Cas9-reactive T cells within the adult human population","investigator":"Schmueck-Henneresse, Michael","investigatorInstitution":"Institute for Medical Immunology","publicationName":"Nature Medicine","researchArea":"Response to Therapeutic Agent","prettyUrls":{"91":"wagner-2018-naturemedicine"},"prettyUrlList":["wagner-2018-naturemedicine"],"summary":"The discovery of the highly efficient site-specific nuclease system CRISPR/Cas9 from Streptococcus (S). pyogenes has galvanized the field of gene therapy. Immunogenicity of Cas9 nuclease was demonstrated in mice. Pre-existing immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear, whether this induces a pre-existing T-cell memory against the Cas9 nuclease. Here, we show the presence of a ubiquitous pre-existing memory/effector T-cell response directed towards the most popular Cas9 homolog from S. pyogenes (SpCas9) within healthy human subjects. We characterized SpCas9-reactive T-cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity and lineage determination. In depth analysis of the SpCas9-reactive T-cells revealed a high frequency of SpCas9-reactive regulatory T-cells that were able to mitigate SpCas9-reactive effector T-cell proliferation and function in vitro. Our results shed light on the T-cell mediated immunity towards CRISPR-associated nucleases and offer a possible solution to overcome the problem of pre-existing immunity.","prettyUrl":"wagner-2018-naturemedicine","following":false,"created":"10/23/2018","featured":false,"publishedDate":"10/23/2018","urlOrId":"wagner-2018-naturemedicine","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e5b8e407-62d8-4332-ba99-7821295fa5f7","title":"Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus.","investigator":"Antoine Toubert","investigatorInstitution":"INSERM U1160","publicationName":"Science Translational Medicine","researchArea":"Basic Immunology","prettyUrls":{"89":"clave-2018-scitransmed"},"prettyUrlList":["clave-2018-scitransmed"],"summary":"The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.","prettyUrl":"clave-2018-scitransmed","following":false,"created":"10/02/2018","featured":false,"publishedDate":"10/08/2018","urlOrId":"clave-2018-scitransmed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a73e35bb-e4dd-4d52-a894-0693cd14ca8c","title":"High throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in Alopecia Areata","investigator":"de Jong, Annemieke","investigatorInstitution":"Department of Dermatology","publicationName":"Journal of Clinical Investigation Insight","researchArea":"Dermatology","prettyUrls":{"88":"dejong-2018-jciinsight"},"prettyUrlList":["dejong-2018-jciinsight"],"summary":"Alopecia Areata (AA) is an autoimmune disease in which cytotoxic T-cells specifically target growing hair follicles. We used high throughput TCR sequencing in the C3H/HeJ mouse model of AA and in human AA patients to gain insight into pathogenic T-cell populations and their dynamics, which revealed clonal CD8+ T cell expansions in lesional skin. In the C3H/HeJ model we observed inter-individual sharing of TCRβ chain protein sequences, which strongly supports a model of antigenic drive in AA. The overlap between the lesional TCR repertoire and a population of CD8+NKG2D+ T cells in skin-draining lymph nodes identified this subset as pathogenic effectors. In AA patients, treatment with oral JAK-inhibitor tofacitinib resulted in a decrease in clonally expanded CD8+ T cells in the scalp, but also revealed that many expanded lesional T cell clones do not completely disappear from either skin or blood during treatment with tofacitinib, which may explain in part the relapse of disease after stopping treatment.","prettyUrl":"dejong-2018-jciinsight","following":false,"created":"08/14/2018","featured":false,"publishedDate":"10/04/2018","urlOrId":"dejong-2018-jciinsight","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e7393ffb-013d-471d-9ce1-3adadd9ca079","title":"CD4+ and CD8+ autoreactive T cells in narcolepsy patients target self-antigens of hypocretin-producing neurons","investigator":"Sallusto, Federica","investigatorInstitution":"Center of Medical Immunology, Institute for Research in Biomedicine","publicationName":"Nature","researchArea":"Autoimmune Disorders","prettyUrls":{"87":"latorre-2018-nature"},"prettyUrlList":["latorre-2018-nature"],"summary":"Narcolepsy is a rare chronic sleep disorder caused by the selective loss of neuronal cells of the lateral hypothalamus that produce the neuropeptide hypocretin (HCRT). The strong genetic association with the HLA-DQB1*06:02 haplotype, the evidence for immune dysregulation and the increased disease incidence upon flu vaccination, suggest that narcolepsy is an autoimmune disease that manifest in genetically predisposed individuals upon triggering by environmental factors. However, to date there is no evidence for autoreactive lymphocytes in narcolepsy patients. Here, we used two methods to interrogate the T-cell repertoire of narcolepsy patients and show that memory CD4+ T cells specific for HCRT were present in 19 out of 19 patients but only in 3 out of 10 control donors. Memory CD4+ T cells specific for TRIB2, another self-antigen expressed by HCRT neurons, were also found in 8 out of 13 patients. By isolating a large panel of T cell clones, we demonstrate that HCRT- and TRIB2-specific CD4+ T cells are polyclonal, target multiple epitopes, are restricted primarily by HLA-DR molecules and do not cross-react with influenza antigens. Of note, most autoreactive CD4+ T cells respond to exogenous peptides but failed to respond to whole proteins, suggesting that the recognized epitopes are generated by extracellular processing. High throughput TCR sequencing identified clonotypes of autoreactive T cells present in blood of the same and, in some cases, of different patients, pointing to the existence of public clonotypes in narcolepsy. Finally, HCRT-reactive memory CD8+ T cells could be also detected in the blood and cerebrospinal fluid (CSF) of narcolepsy patients. Collectively, these findings solidify the autoimmune etiology of narcolepsy by identifying CD4+ and CD8+ T cell reactivity against HCRT neurons, providing the basis for new approaches to the rapid diagnosis and therapy of this disabling disease.","prettyUrl":"latorre-2018-nature","following":false,"created":"08/07/2018","featured":false,"publishedDate":"09/20/2018","urlOrId":"latorre-2018-nature","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9f837d18-0af2-4532-94a9-a3bf99bcbe6a","title":"Induction of Resistance to Chimeric Antigen Receptor (CAR) T cell Therapy by Transduction of a Single Leukemic B Cell","investigator":"Melenhorst, Jan Joseph","investigatorInstitution":"University of Pennsylvania, Center for Cellular Immunotherapies","publicationName":"Nature Medicine","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"86":"ruella-2018-naturemedicine"},"prettyUrlList":["ruella-2018-naturemedicine"],"summary":"We report a patient treated with CTL019 (tisagenlecleucel, KymriahTM) who relapsed nine months after CAR T cell infusion with CD19-negative leukemia that aberrantly expressed the anti-CD19 CAR protein. The CAR19 gene was unintentionally introduced into a single leukemic B cell during CTL019 manufacturing, and the protein expressed on the surface of leukemic cells bound in cis to the CD19 epitope, masking it from recognition by CTL019 T-cells and leading to resistance. This case further illustrates that the progeny of a subclone of the parental leukemia generated during the cell manufacturing process can lead to a late relapse of leukemia.","prettyUrl":"ruella-2018-naturemedicine","following":false,"created":"07/11/2018","featured":false,"publishedDate":"08/08/2018","urlOrId":"ruella-2018-naturemedicine","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"dd2d6613-f219-4464-b651-95531ebbdd31","title":"Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis","investigator":"Jelcic, Ivan","investigatorInstitution":"Neuroimmunology and MS Research Section (nimsNIMS), Neurology Clinic, University of Zurich, University Hospital Zurich,","publicationName":"Cell","researchArea":"Autoimmune Disorders","prettyUrls":{"85":"jelcic-2018-cell"},"prettyUrlList":["jelcic-2018-cell"],"summary":"Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic-, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in an HLA-DR dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.  These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.","prettyUrl":"jelcic-2018-cell","following":false,"created":"07/30/2018","featured":false,"publishedDate":"08/01/2018","urlOrId":"jelcic-2018-cell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"102029c0-d634-4a96-9af2-c792190e27ea","title":"Co-expression of CD39 and CD103 identifies tumor-reactive CD8 tumor-infiltrating lymphocytes in human solid tumors","investigator":"Duhen, Thomas","investigatorInstitution":"AgonOx, Inc.","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"83":"duhen-2018-natcomms"},"prettyUrlList":["duhen-2018-natcomms"],"summary":"Identifying tumor antigen-specific T cells from cancer patients has important implications forimmunotherapy diagnostics and therapeutics. Here we show that CD103+CD39+ tumor infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103+CD39+ CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103+CD39+ CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that may help define mechanisms of existing immunotherapy treatments, and may help develop future adoptive T-cell cancer therapies.","prettyUrl":"duhen-2018-natcomms","following":false,"created":"06/21/2018","featured":false,"publishedDate":"07/13/2018","urlOrId":"duhen-2018-natcomms","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"496b4b22-5fdc-4d4f-baa4-ecf20e8c290e","title":"A diverse lipid antigen-specific T cell receptor repertoire is clonally expanded during active tuberculosis","investigator":"Seshadri, Chetan","investigatorInstitution":"Department of Medicine","publicationName":"Journal of Immunology","researchArea":"Infectious Disease","prettyUrls":{"82":"seshadri-2018-journalofimmunology"},"prettyUrlList":["seshadri-2018-journalofimmunology"],"summary":"Human T cells that recognize lipid antigens presented by highly conserved CD1 proteins often express semi-invariant T cell receptors (TCRs), but the true diversity of lipid antigen-specific TCRs remains unknown.  We use CD1b tetramers and high-throughput immunosequencing to analyze thousands of TCRs from ex vivo sorted or in vitro expanded T cells specific for the mycobacterial lipid antigen, glucose monomycolate (GMM).  Our results reveal a surprisingly diverse repertoire resulting from editing of germline encoded gene rearrangements analogous to MHC-restricted TCRs.   We used a distance-based metric (TCRdist) to show how this diverse TCR repertoire builds upon previously reported conserved motifs by including subject-specific TCRs.  In a South African cohort, we show that TCRdist can identify clonal expansion of diverse GMM-specific TCRs and accurately distinguish patients with active tuberculosis from control subjects.  These data suggest that the similar mechanisms govern the selection and expansion of peptide and lipid antigen-specific T cells despite the non-polymorphic nature of CD1 in Homo sapiens.","prettyUrl":"seshadri-2018-journalofimmunology","following":false,"created":"12/05/2016","featured":false,"publishedDate":"05/24/2018","urlOrId":"seshadri-2018-journalofimmunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"915af45d-b80d-4f1f-aa89-a03c02caada0","title":"Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development","investigator":"Ott de Bruin, Lisa M","investigatorInstitution":"Division of Immunology","publicationName":"Blood","researchArea":"Basic Immunology","prettyUrls":{"81":"ottdebruin-2018-blood"},"prettyUrlList":["ottdebruin-2018-blood"],"summary":"Hypomorphic RAG1 mutations allowing residual T and B cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T and B cell repertoire. In order to examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with equivalent mutations found in patients with CID-G/AI. By using high throughput sequencing, we identified marked skewing of Igh V and Trb V gene usage in early progenitors, with a bias for productive Igh and Trb rearrangements after selection occurred and increased apoptosis of B cell progenitors. Rearrangement at the Igk locus was impaired, and polyreactive IgM antibodies were detected. This study provides novel insights in how these hypomorphic Rag1 mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.","prettyUrl":"ottdebruin-2018-blood","following":false,"created":"12/07/2017","featured":false,"publishedDate":"05/07/2018","urlOrId":"ottdebruin-2018-blood","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fbf87883-dc0c-4dec-8261-a3babe3b7002","title":"Patients with CD3G mutations reveal a role for human CD3g in Treg diversity and suppressive function","investigator":"Rowe, Jared H","investigatorInstitution":"Division of Hematology-Oncology","publicationName":"Blood","researchArea":"Basic Immunology","prettyUrls":{"80":"rowe-2018-blood"},"prettyUrlList":["rowe-2018-blood"],"summary":"Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor β (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.","prettyUrl":"rowe-2018-blood","following":false,"created":"02/23/2018","featured":false,"publishedDate":"04/02/2018","urlOrId":"rowe-2018-blood","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2588b313-61d5-4cab-9e07-0a6c7f746b46","title":"Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells","investigator":"Melenhorst , Joseph J","investigatorInstitution":"Center for Cellular Immunotherapies","publicationName":"Nature","researchArea":"Cancer Immunotherapy","prettyUrls":{"79":"melenhorst-cll-ctl019"},"prettyUrlList":["melenhorst-cll-ctl019"],"summary":"Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient’s second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient’s CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.","prettyUrl":"melenhorst-cll-ctl019","following":false,"created":"03/30/2018","featured":false,"publishedDate":"03/30/2018","urlOrId":"melenhorst-cll-ctl019","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"002fe3b9-1d83-4809-a01e-c541002d9a67","title":"T-cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: an exploratory proof-of-principle study","investigator":"Lang Kuhs, Krystle A","investigatorInstitution":"Vanderbilt University Medical Center","publicationName":"PLOSone","researchArea":"Infectious Disease","prettyUrls":{"78":"langkuhs-2018-plosone"},"prettyUrlList":["langkuhs-2018-plosone"],"summary":"Background: It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer.  Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer.  We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16. \n\nMethods: TCR repertoires of women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n=25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n=25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n=51], D [n=2], J [n=13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status.  \n\nResults: TCR repertoire richness was associated with CIN3+ status (P=0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V-gene (TRBV6-7) was significantly associated with CIN3+ status (RA=0.11%, 0.16%, among cases and controls, respectively, Bonferroni P=0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90).  \n\nConclusions: Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed. \n\n Impact: This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection.  These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection.","prettyUrl":"langkuhs-2018-plosone","following":false,"created":"01/05/2018","featured":false,"publishedDate":"03/28/2018","urlOrId":"langkuhs-2018-plosone","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a4012733-8c6a-4b46-93eb-5b7c7315c8e2","title":"Alloreactive T Cell Receptor Diversity against Structurally Similar or Dissimilar HLA-DP Antigens Assessed by Deep Sequencing","investigator":"Arrieta-Bolaños, Esteban","investigatorInstitution":"Institute for Experimental Cellular Therapy","publicationName":"Frontiers in Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"77":"bolanos-2018-frontiersinimmunology"},"prettyUrlList":["bolanos-2018-frontiersinimmunology"],"summary":"T cell alloreactivity is mediated by a self-human leukocyte antigen (HLA)-restricted T cell receptor (TCR) repertoire able to recognize both structurally similar and dissimilar allo- geneic HLA molecules (i.e., differing by a single or several amino acids in their peptide- binding groove). We hypothesized that thymic selection on self-HLA molecules could have an indirect impact on the size and diversity of the alloreactive response. To test this possibility, we used TCR Vβ immunophenotyping and immunosequencing technology in a model of alloreactivity between self-HLA selected T cells and allogeneic HLA-DPB1 (DPB1) differing from self-DPB1*04:02 by a single (DPB1*02:01) or several (DPB1*09:01) amino acids in the peptide-binding groove. CD4+ T cells from three different self- DPB1*04:01,*04:02 individuals were stimulated with HeLa cells stably transduced with the relevant peptide processing machinery, co-stimulatory molecules, and HLA-DP. Flow cytometric quantification of the DPB1-specific T cell response measured as upregulation of the activation marker CD137 revealed significantly lower levels of alloreactivity against DPB1*02:01 compared with DPB1*09:01 (mean CD4+CD137+ frequency 35.2 ± 9.9 vs. 61.5 ± 7.7%, respectively, p < 0.0001). These quantitative differences were, how- ever, not reflected by differences in the breadth of the alloreactive response at the Vβ level, with both alloantigens eliciting specific responses from all TCR-Vβ specificities tested by flow cytometry, albeit with higher levels of reactivity from most Vβ specificities against DPB1*09:01. In line with these observations, TCRB-CDR3 immunosequencing showed no significant differences in mean clonality of sorted CD137+CD4+ cells allo- reactive against DPB1*02:01 or DPB1*09:01 [0.39 (0.36–0.45) and 0.39 (0.30–0.46), respectively], or in the cumulative frequencies of the 10 most frequent responding clones (55–67 and 58–62%, respectively). Most of the clones alloreactive against DPB1*02:01 (68.3%) or DPB1*09:01 (75.3%) were characterized by low-abundance (i.e., they were not appreciable among the pre-culture T cells). Interestingly, however, their cumulative frequency was lower against DPB1*02:01 compared with DPB1*09:01 (mean cumulative frequency 35.3 vs. 50.6%, respectively). Our data show that, despite lower levels of alloreactivity, a similar clonal diversity can be elicited by structurally similar compared with structurally dissimilar HLA-DPB1 alloantigens and demonstrate the power of TCRB immunosequencing in unraveling subtle qualitative changes not appreciable by conventional methods.","prettyUrl":"bolanos-2018-frontiersinimmunology","following":false,"created":"03/15/2018","featured":false,"publishedDate":"03/15/2018","urlOrId":"bolanos-2018-frontiersinimmunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"94dab90a-7d46-47bc-9295-a61de919f258","title":"Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo","investigator":"Kooreman, Nigel G","investigatorInstitution":"Institute for Stem Cell Biology and Regenerative Medicine/Stanford Cardiovascular Institute of Medicine","publicationName":"Cell Stem Cell","researchArea":"Cancer Immunotherapy","prettyUrls":{"76":"kooreman-2018-cellstemcell"},"prettyUrlList":["kooreman-2018-cellstemcell"],"summary":"Cancer cells and embryonic tissues share a number of cellular and molecular properties, suggesting that induced pluripotent stem cells (iPSCs) may be harnessed to elicit anti-tumor responses in cancer vaccines. RNA sequencing revealed that human and murine iPSCs express tumor-associated antigens, and we show here a proof of principle for using irradiated iPSCs in autologous anti-tumor vaccines. In a prophylactic setting, iPSC vaccines prevent tumor growth in syngeneic murine breast cancer, mesothelioma, and melanoma models. As an adjuvant, the iPSC vaccine inhibited melanoma recurrence at the resection site and reduced metastatic tumor load, which was associated with fewer Th17 cells and increased CD11b+GR1hi myeloid cells. Adoptive transfer of T cells isolated from vaccine-treated tumor-bearing mice inhibited tumor growth in unvaccinated recipients, indicating that the iPSC vaccine promotes an antigen-specific anti-tumor T cell response. Our data suggest an easy, generalizable strategy for multiple types of cancer that could prove highly valuable in clinical immunotherapy.","prettyUrl":"kooreman-2018-cellstemcell","following":false,"created":"12/26/2017","featured":false,"publishedDate":"02/15/2018","urlOrId":"kooreman-2018-cellstemcell","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"52a7853d-37e4-416b-b51e-d77525b5746a","title":"Contraction of T cell richness in lung cancer brain metastases","investigator":"Mansfield, Aaron S","investigatorInstitution":"Division of Medical Oncology","publicationName":"Scientific Reports","researchArea":"Cancer","prettyUrls":{"75":"mansfield-2018-scientificreports"},"prettyUrlList":["mansfield-2018-scientificreports"],"summary":"Very little is known about how the adaptive immune system responds to clonal evolution and tumor heterogeneity in non-small cell lung cancer. We profiled the T-cell receptor β complementarity determining region 3 in 20 patients with fully resected non-small cell lung cancer primary lesions and paired brain metastases. We characterized the richness, abundance and overlap of T cell clones between pairs, in addition to the tumor mutation burden and predicted neoantigens. We found a significant contraction in the number of unique T cell clones in brain metastases compared to paired primary cancers. The vast majority of T cell clones were specific to a single lesion, and there was minimal overlap in T cell clones between paired lesions. Despite the contraction in the number of T cell clones, brain metastases had higher non-synonymous mutation burdens than primary lesions. Our results suggest that there is greater richness of T cell clones in primary lung cancers than their paired metastases despite the higher mutation burden observed in metastatic lesions. These results may have implications for immunotherapy.","prettyUrl":"mansfield-2018-scientificreports","following":false,"created":"12/26/2017","featured":false,"publishedDate":"02/07/2018","urlOrId":"mansfield-2018-scientificreports","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"53a853f1-b11d-442a-803d-54092d60da67","title":"T cell phenotype and T cell receptor repertoire in untreated patients with major depressive disorder","investigator":"Gold, Stefan","investigatorInstitution":"Institute of Neuroimmunology and Multiple Sclerosis (INIMS), Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Germany","publicationName":"Frontiers in Immunology","researchArea":"Basic Immunology","prettyUrls":{"74":"patas-2018-frontiersinimmunology"},"prettyUrlList":["patas-2018-frontiersinimmunology"],"summary":"While a link between inflammation and the development of neuropsychiatric disorders, including major depressive disorder (MDD) is supported by a growing body of evidence, little is known about the contribution of aberrant adaptive immunity in this context. Here, we conducted in-depth characterization of T cell phenotype and T cell receptor (TCR) repertoire in MDD. For this cross-sectional case-control study, we recruited antidepressant-free patients with MDD without any somatic or psychiatric comorbidities (n = 20), who were individually matched for sex, age, body mass index, and smoking status to a non-depressed control subject (n = 20). T cell phenotype and repertoire were interrogated using a combination of flow cytometry, gene expression analysis, and next generation sequencing. T cells from  \nMDD patients showed significantly lower surface expression of the chemokine receptors CXCR3 and CCR6, which are known to be central to T cell differentiation and trafficking. In addition, we observed a shift within the CD4+ T cell compartment characterized by a higher frequency of CD4+CD25highCD127low/− cells and higher FOXP3 mRNA expression in purified CD4+ T cells obtained from patients with MDD. Finally, flow cytometry-based TCR V repertoire analysis indicated a less diverse  \nCD4+ T cell repertoire in MDD, which was corroborated by next generation sequencing of the TCR β chain CDR3 region. Overall, these results suggest that T cell phenotype and TCR utilization are skewed on several levels in patients with MDD. Our study identifies putative cellular and molecular signatures of dysregulated adaptive immunity and reinforces the notion that T cells are a pathophysiologically  \nrelevant cell population in this disorder.","prettyUrl":"patas-2018-frontiersinimmunology","following":false,"created":"02/01/2018","featured":false,"publishedDate":"02/01/2018","urlOrId":"patas-2018-frontiersinimmunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"cdd13b85-e83d-4384-9a39-0f91d5b53c39","title":"Hepatitis E virus-induced primary cutaneous CD30+ T cell lymphoproliferative disorder","investigator":"Mallet, Vincent","investigatorInstitution":"Cochin Hospital","publicationName":"Journal of Hepatology","researchArea":"Infectious Disease","prettyUrls":{"73":"mallet-2017-journalofhepatology"},"prettyUrlList":["mallet-2017-journalofhepatology"],"summary":"BACKGROUND & AIM: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality.\n\nMETHODS: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver.\n\nRESULTS: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVβ signature skewed towards Vβ4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes.\n\nCONCLUSION: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals.\n\nLAY SUMMARY: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.","prettyUrl":"mallet-2017-journalofhepatology","following":false,"created":"05/22/2017","featured":false,"publishedDate":"01/25/2018","urlOrId":"mallet-2017-journalofhepatology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ec74f507-d3e9-4fd1-ac3a-fc5f7ba4db82","title":"T-cell receptor sequencing of early stage breast cancer tumors identifies altered clonal structure of the T-cell repertoire","investigator":"Quake, Stephen R.","investigatorInstitution":"Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA, USA","publicationName":"PNAS","researchArea":"Cancer","prettyUrls":{"66":"beausang-2017-pnas"},"prettyUrlList":["beausang-2017-pnas"],"summary":"Tumor infiltrating T-cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T-cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T-cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T-cell beta chain repertoire in 16 patients with early stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing approximately 3-fold more T-cells, but with a lower fraction of unique sequences and higher clonality compared to normal breast. The clonal structure of T-cells in blood and normal breast is more similar than between blood and tumor and can be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T-cells overlap between tissues from the same patient, including approximately 50% of T-cells between tumor and normal breast. Both solid tissues contain high-abundance “enriched” sequences that are absent or of low abundance in the other tissue. Many of these T-cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T-cells in both tumor and normal breast. Enriched T-cell sequences are typically unique to each patient, but there is a subset of sequences that are shared between many different patients. We show that most of these are commonly generated sequences and thus unlikely to play an important role in the tumor microenvironment.","prettyUrl":"beausang-2017-pnas","following":false,"created":"08/22/2017","featured":false,"publishedDate":"01/25/2018","urlOrId":"beausang-2017-pnas","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b9312d2d-baa5-4435-8888-5f41e184ae65","title":"T-cell receptor β chains show abnormal shortening, repertoire diversity and sharing in type 1 diabetes","investigator":"Peakman, Mark","investigatorInstitution":"Department of Immunobiology, Faculty of Life Sciences & Medicine","publicationName":"Nature Communications","researchArea":"Autoimmune Disorders","prettyUrls":{"72":"peakman-2017-naturecommunications"},"prettyUrlList":["peakman-2017-naturecommunications"],"summary":"Defects in T-cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. To address this hypothesis, >2x108 TCRB sequences were obtained from circulating true naïve, central memory, regulatory and stem-cell like CD4+ T-cell subsets from subjects with type 1 diabetes and healthy donors. Analysis reveals that type 1 diabetes subjects have shorter complementarity-determining-region-3s in all cell subsets, due to increased deletions/reduced insertions during VDJ rearrangement. Enhanced shortness is also observed in unproductive TCR sequences, generated before thymic culling, suggesting it arises independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T-cells are significantly shorter compared with anti-viral T-cells and with CDR3B length distributions obtained by deep sequencing from healthy donors. Thus, early events in thymic T-cell development and repertoire generation are abnormal in type 1 diabetes. Enhanced shortness suggests a model of autoimmune disease risk arising from generalized, heightened potential for self-recognition by T-cells.","prettyUrl":"peakman-2017-naturecommunications","following":false,"created":"06/12/2017","featured":false,"publishedDate":"01/16/2018","urlOrId":"peakman-2017-naturecommunications","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"521d04e6-3bbd-4a04-858b-ba64550dcb14","title":"Memory CD4+ T cell receptor repertoire data mining as a tool for identifying cytomegalovirus serostatus","investigator":"Ogunjimi, Benson","investigatorInstitution":"University of Antwerp","publicationName":"Genes and Immunology","researchArea":"Infectious Disease","prettyUrls":{"71":"deneuter-2018-cmvserostatus"},"prettyUrlList":["deneuter-2018-cmvserostatus"],"summary":"Pathogens of past and current infections have been identified directly by means of PCR or indirectly by measuring a specific immune response (e.g. antibody titration). Using a novel approach, Emerson and colleagues showed that the cytomegalovirus serostatus can also be accurately determined by using a T cell receptor repertoire data mining approach. In this study, we have sequenced the CD4+ memory T cell receptor repertoire of a Belgian cohort with known cytomegalovirus serostatus. A random forest classifier was trained on the CMV specific T cell receptor repertoire signature and used to classify individuals in the Belgian cohort. This study shows that the novel approach can be reliably replicated with an equivalent performance as that reported by Emerson and colleagues. Additionally, it provides evidence that the T cell receptor repertoire signature is to a large extent preserved in the CD4+ memory repertoire.","prettyUrl":"deneuter-2018-cmvserostatus","following":false,"created":"01/15/2018","featured":false,"publishedDate":"01/16/2018","urlOrId":"deneuter-2018-cmvserostatus","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ab8130ab-a500-4c92-9055-379aed8d3280","title":"Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells","investigator":"Rudqvist, Nils-Petter","investigatorInstitution":"Weill Cornell Medicine","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"68":"rudqvist-2017-cancerimmunologyresearch"},"prettyUrlList":["rudqvist-2017-cancerimmunologyresearch"],"summary":"Immune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti–CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCR CDR3 region. The combined treatment increased TIL density and CD8/CD4 ratio.  Assessment of the frequency of T cell clones indicated that anti–CTLA-4 resulted in fewer clones and a more oligoclonal repertoire compared to untreated tumors. In contrast, RT increased the CD8/CD4 ratio and broadened the TCR repertoire, and when used in combination with anti–CTLA-4, these selected T cell clones proliferated. Hierarchical clustering of CDR3 sequences showed a treatment-specific clustering of TCRs that were shared by different mice. Abundant clonotypes were commonly shared between animals and yet treatment-specific. Analysis of amino-acid sequence similarities revealed a significant increase in the number and richness of dominant CDR3 motifs in tumors treated with RT+anti–CTLA-4 compared to control. The repertoire of TCRs reactive with a single tumor antigen recognized by CD8+ T cells was heterogeneous but highly clonal, irrespective of treatment. Overall, data support a model whereby a diverse TCR repertoire is required to achieve tumor rejection and may underlie the synergy between RT and CTLA-4 blockade.","prettyUrl":"rudqvist-2017-cancerimmunologyresearch","following":false,"created":"11/02/2017","featured":false,"publishedDate":"01/04/2018","urlOrId":"rudqvist-2017-cancerimmunologyresearch","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9fb1cbc0-0421-475b-ab3d-f97fc1a1d72b","title":"Public clonotypes and convergent recombination characterize the naïve CD8+ T-cell receptor (TCR) repertoire of extremely preterm neonates.","investigator":"Carey, Alison J","investigatorInstitution":"Departments of Pediatrics and Microbiology and Immunology","publicationName":"Frontiers in Immunology","researchArea":"Basic Immunology","prettyUrls":{"70":"carey-2017-frontiersinimmunology"},"prettyUrlList":["carey-2017-frontiersinimmunology"],"summary":"Respiratory support improvements have aided survival of premature neonates, but infection susceptibility remains a predominant problem. We previously reported that neonatal mice have a rapidly-evolving T-cell receptor (TCR) repertoire that impairs CD8+ T cell immunity. To understand the impact of prematurity on the human CD8+ TCR repertoire, we performed next generation sequencing (NGS) of the complementarity-determining region 3 (CDR3) from the rearranged TCR variable beta (Vβ) in sorted, naïve CD8+ T cells from extremely preterm neonates (23-27 weeks gestation), term neonates (37-41 weeks gestation), children (16-56 months) and adults (25-50 years old). Strikingly, preterm neonates had an increased frequency of public clonotypes shared between unrelated individuals. Public clonotypes identified in preterm infants were encoded by germ line gene sequences, and some of these clonotypes persisted into adulthood.  The preterm neonatal naïve CD8+ TCR repertoire exhibited convergent recombination, characterized by different nucleotide sequences encoding the same amino acid CDR3 sequence.  As determined by Pielou's evenness and iChao1 metrics, extremely preterm neonates have less clonality, but also have a much lower bound for the number of unique TCR within an individual preterm neonate, which indicates a less rich and diverse repertoire, as compared to term neonates, children and adults. This suggests that T cell selection in the preterm neonate may be less stringent or different. Our analysis is the first to compare the TCR repertoire of naïve CD8+ T cells between viable preterm neonates and term neonates. We find preterm neonates have a repertoire immaturity which potentially contributes to their increased infection susceptibility. A developmentally-regulated, evenly distributed repertoire in preterm neonates may lead to the inclusion of public TCR CDR3β sequences that overlap between unrelated individuals in the preterm repertoire.","prettyUrl":"carey-2017-frontiersinimmunology","following":false,"created":"12/19/2017","featured":false,"publishedDate":"12/19/2017","urlOrId":"carey-2017-frontiersinimmunology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f32906ae-97bc-48c2-b394-0dca55523fa1","title":"Abnormalities of T cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: implications for autoimmunity","investigator":"Rowe, Jared H","investigatorInstitution":"Division of Immunology, Boston Children’s Hospital","publicationName":"Journal of Allergy and Clinical Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"62":"rowe-2017-jallergyclinimmunol"},"prettyUrlList":["rowe-2017-jallergyclinimmunol"],"summary":"Capsule Summary:\nHypomorphic RAG mutations in humans cause abnormalities of the T cell repertoire that involve both conventional and regulatory T cells, and may contribute to the increased risk of autoimmunity.\n\nTo the Editor:\nHuman RAG1/2 gene mutations are associated with a spectrum of clinical and\nimmunological phenotypes. While null RAG mutations cause severe combined immune deficiency (SCID), hypomorphic mutations may induce Omenn syndrome (OS), atypical SCID (AS), or combined immunodeficiency (CID) manifesting with autoimmunity. We have previously demonstrated that in patients with RAG mutations the severity of the clinical phenotype correlates with the residual levels of RAG protein recombination activity and T/B cell repertoire diversity and composition; however, whether there are molecular signatures indicative of autoimmunity remains unknown. Regulatory T (Treg) cells play a key role in preventing autoimmunity. While numerical and functional Treg defects have been demonstrated in OS patients, no data are available for patients with CID/AS despite the frequent association with autoimmunity.","prettyUrl":"rowe-2017-jallergyclinimmunol","following":false,"created":"08/03/2017","featured":false,"publishedDate":"12/07/2017","urlOrId":"rowe-2017-jallergyclinimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"35ee1166-bfba-40a9-871b-2c6d6ab7f1c9","title":"Tumor-infiltrating Merkel cell polyomavirus-specific T cells are diverse and associated with improved patient survival","investigator":"Miller, Natalie J","investigatorInstitution":"Dermatology/Medicine/Pathology","publicationName":"Cancer Immunology Research","researchArea":"Cancer","prettyUrls":{"69":"miller-2017-cancerimmunologyresearch"},"prettyUrlList":["miller-2017-cancerimmunologyresearch"],"summary":"Tumor-infiltrating CD8+ T cells are associated with improved survival of patients with Merkel cell carcinoma (MCC), an aggressive skin cancer causally linked to Merkel cell polyomavirus (MCPyV). However, CD8+ T-cell infiltration is robust in only 4% to 18% of MCC tumors. We characterized the T-cell receptor (TCR) repertoire restricted to one prominent epitope of MCPyV (KLLEIAPNC, \"KLL\") and assessed whether TCR diversity, tumor infiltration, or T-cell avidity correlated with clinical outcome. HLA-A002:01/KLL tetramerþ CD8+ T cells from MCC patient peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) were isolated via flow cytometry. TCRb (TRB) sequencing was performed on tetramer+ cells from PBMCs or TILs (n=14) and matched tumors (n=12). Functional avidity of T-cell clones was determined by IFNg production. We identified KLL tetramer+ T cells in 14% of PBMC and 21% of TIL from MCC patients. TRB repertoires were strikingly diverse (397 unique TRBs were identified from 12 patients) and mostly private (only one TCRb clonotype shared between two patients). An increased fraction of KLL-specific TIL (>1.9%) was associated with significantly increased MCC-specific survival P =0.0009). T-cell cloning from four patients identified 42 distinct KLL-specific TCRa/b pairs. T-cell clones from patients with improved MCC-specific outcomes were more avid (P < 0.05) and recognized an HLA- appropriate MCC cell line. T cells specific for a single MCPyV epitope display marked TCR diversity within and between patients. Intratumoral infiltration by MCPyV-specific T cells was associated with significantly improved MCC-specific survival, suggesting that augmenting the number or avidity of virus- specific T cells may have therapeutic benefit.\n\nSome of the sequencing was funded through the Adaptive Biotechnologies Young Investigator Award. Those samples are included in this dataset.","prettyUrl":"miller-2017-cancerimmunologyresearch","following":false,"created":"11/16/2017","featured":false,"publishedDate":"11/16/2017","urlOrId":"miller-2017-cancerimmunologyresearch","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"0cf5c4ea-a59b-4ea9-afd3-35b4fccdb5bb","title":"Generation of higher affinity T cell receptors by antigen-driven differentiation of progenitor T cells in vitro","investigator":"Greenberg, Philip D","investigatorInstitution":"Fred Hutchinson Cancer Research Center, Dept. of Immunology","publicationName":"Nature Biotechnology","researchArea":"Adoptive T Cell Therapy","prettyUrls":{"64":"schmitt-2017-naturebiotechnology"},"prettyUrlList":["schmitt-2017-naturebiotechnology"],"summary":"Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low-avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs. The approach takes advantage of natural Tcrb gene rearrangement to generate diversity in the length and composition of CDR3β. In vitro differentiation of progenitors transduced with a known Tcra gene in the presence of antigen drives differentiation of cells with a distinct agonist-selected phenotype. We purified these cells to generate TCRβ chain libraries pre-enriched for target antigen specificity. Several TCRβ chains paired with a transgenic TCRα chain to produce a TCR with higher affinity than the parental TCR for target antigen, without evidence of cross-reactivity","prettyUrl":"schmitt-2017-naturebiotechnology","following":false,"created":"06/29/2017","featured":false,"publishedDate":"11/13/2017","urlOrId":"schmitt-2017-naturebiotechnology","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9df86839-3f40-4c2d-b361-477bf7f363ea","title":"T-cell localization, activation and clonal expansion in human pancreatic ductal adenocarcinoma","investigator":"Greenberg, Phil","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"65":"stromnes-2017-cancerimmunologyresearch"},"prettyUrlList":["stromnes-2017-cancerimmunologyresearch"],"summary":"Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared to stroma and tumor cell nests. Tumors containing more CD8+ T cells also had increased granulocytes, CD163+ (M2 immunosuppressive phenotype) macrophages, and FoxP3+ regulatory T cells. PD-L1 was rare on tumor cells, but was expressed by CD163+ macrophages and an additional stromal cell subset commonly found clustered together adjacent to tumor epithelium. The majority of tumoral CD8+ T cells did not express molecules suggestive of recent T-cell receptor (TCR) signaling. However, 41BB+PD-1+ T cells were still significantly enriched in tumors compared to circulation. Tumoral PD-1+ CD8+ T cells commonly expressed additional inhibitory receptors, but did not appear terminally exhausted as reflected by T-bet and Eomes expression. Analysis of gene expression and rearranged TCR genes by deep sequencing suggested most patients have a limited tumor-reactive T-cell response. Multiplex immunohistochemistry revealed variable T-cell infiltration based on abundance and location, which may result in different mechanisms of immunotherapy resistance. Overall, the data support the need for therapies that either induce endogenous, or provide engineered, tumor-specific T-cell responses and concurrently relieve suppressive mechanisms operative at the tumor site.","prettyUrl":"stromnes-2017-cancerimmunologyresearch","following":false,"created":"09/08/2017","featured":false,"publishedDate":"10/06/2017","urlOrId":"stromnes-2017-cancerimmunologyresearch","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"276f8080-1757-482e-abd4-acf71ce4a1f8","title":"Human TCR-MHC coevolution after divergence from mice includes increased non-template-encoded CDR3 diversity","investigator":"Thomas Blankenstein","investigatorInstitution":"Max-Delbrück-Centrum für Molekulare Medizin/AG Blankenstein","publicationName":"Journal of Experimental Medicine","researchArea":"Basic Immunology","prettyUrls":{"63":"blankenstein-2017-jem"},"prettyUrlList":["blankenstein-2017-jem"],"summary":"For thymic selection and mounting specific responses to pathogens, T cells must interact through their unique αβ T cell antigen receptor (TCR) with peptide-major histocompatibility complex (pMHC) molecules on antigen presenting cells. It is unresolved how the diverse TCRs interact with a multitude of major histocompatibility complex (MHC) molecules as requirement for positive selection. Given the non-random V-J gene usage, it is also unclear how humans generate a larger TCR repertoire than mice. We employed mice containing the entire human TCR gene loci and compared the TCR repertoire in CD4 T cells selected by a single mouse or human MHC class II (MHC II). Compared to mouse MHC II, human MHC II yielded higher thymic output and generated a more diverse TCR repertoire. Comparing the pre- and post-selection repertoire revealed that complementarity determining region 3 (CDR3) length adjusted for apparently different inherent V segment affinity to MHC II. Humans evolved for higher non-template encoded CDR3 diversity compared to mice. Our data demonstrate human TCR-MHC coevolution after divergence from rodents, explain the higher T cell diversity in humans and suggest a mechanism ensuring that basically any V-J gene combination can be selected by a single MHC II molecule.","prettyUrl":"blankenstein-2017-jem","following":false,"created":"08/17/2017","featured":false,"publishedDate":"09/04/2017","urlOrId":"blankenstein-2017-jem","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"807e55e1-42fc-40e0-9ea8-2657addf93db","title":"Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade","investigator":"Dr. Simon J. Dovedi","investigatorInstitution":"MedImmune Ltd","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"59":"dovedi-2017-clincancerres"},"prettyUrlList":["dovedi-2017-clincancerres"],"summary":"Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown.\n\nExperimental Design: The impact of low-dose fractionated RT (5 x 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing (NGS) of the T-cell receptor (TCR)- repertoire. A dual-tumor model was used, with fractionated RT delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field.\n\nResults: We show that fractionated RT leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of pre- existing T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anti-cancer immunity following RT which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T-cells resident in the tumor at the time of RT and infiltrating T-cells.\n\nConclusions: These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.","prettyUrl":"dovedi-2017-clincancerres","following":false,"created":"06/27/2017","featured":false,"publishedDate":"06/28/2017","urlOrId":"dovedi-2017-clincancerres","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5cbaeb57-d23a-422e-a2c2-0ad1d1b8c146","title":"Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis","investigator":"Snyder, Alex","investigatorInstitution":"Departments of Medicine","publicationName":"PLoS Medicine","researchArea":"Cancer Immunotherapy","prettyUrls":{"57":"snyder-2017-plosmedicine"},"prettyUrlList":["snyder-2017-plosmedicine"],"summary":"Background: Inhibition of programmed death-ligand 1 (PD-L1) with atezolizumab can induce durable clinical benefit (DCB) in patients with metastatic urothelial cancers, including complete remissions in patients with chemotherapy refractory disease. Although mutation load and PD-L1 immune cell (IC) staining have been associated with response, they lack sufficient sensitivity and specificity for clinical use. Thus, there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load, predicted neoantigens, and immune cellular infiltration in tumors to enhance our understanding of the biologic underpinnings of response and resistance.\n\nMethods and findings: The goals of this study were to (1) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and (2) determine whether intratumoral and peripheral blood T cell receptor (TCR) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab. We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy. We performed whole exome sequencing (WES), RNA sequencing (RNA-seq), and T cell receptor sequencing (TCR-seq) of pretreatment tumor samples as well as TCR-seq of matched, serially collected peripheral blood, collected before and after treatment with atezolizumab. These parameters were assessed for correlation with DCB (defined as progression-free survival [PFS] >6 months), PFS, and overall survival (OS), both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state.\nPatients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes (TIL) (n = 24, Mann-Whitney p = 0.047). Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS (n = 29, log-rank p = 0.048) and OS (n = 29, log- rank p = 0.011). Patients with DCB also demonstrated more substantial expansion of tumor- associated TCR clones in the peripheral blood 3 weeks after starting treatment (n = 22, Mann-Whitney p = 0.022). The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes (n = 10, hazard ratio (HR) (mean) = 89.88, HR (median) = 23.41, 95% CI [2.43, 506.94], p(HR > 1) = 0.0014). Marked variations in mutation loads were seen with different somatic variant calling methodologies, which, in turn, impacted associations with clinical outcomes. Missense mutation load, predicted neoantigen load, and expressed neoantigen load did not demonstrate significant association with DCB (n = 25, Mann-Whitney p = 0.22, n = 25, Mann-Whitney p = 0.55, and n = 25, Mann-Whitney p = 0.29, respectively). Instead, we found evidence of time-varying effects of somatic mutation load on PFS in this cohort (n = 25, p = 0.044). A limitation of our study is its small sample size (n = 29), a subset of the patients treated on IMvigor 210 (NCT02108652). Given the number of exploratory analyses performed, we intend for these results to be hypothesis-generating.\n\nConclusions: These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors. Incorporating these variables in prospective studies will facilitate identification and treatment of resistant patients.","prettyUrl":"snyder-2017-plosmedicine","following":false,"created":"06/14/2017","featured":false,"publishedDate":"06/20/2017","urlOrId":"snyder-2017-plosmedicine","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5058a0bd-bd73-4db5-b94b-b90dc2a09ba9","title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","investigator":"Diaz, Luis A. Jr","investigatorInstitution":"Memorial Sloan Kettering Cancer Center","publicationName":"Science","researchArea":"Cancer Immunotherapy","prettyUrls":{"56":"diaz-2017-science"},"prettyUrlList":["diaz-2017-science"],"summary":"The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high number of somatic mutations. In a proof-of-concept study, we showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies.  In the current study, we evaluated the efficacy of PD-1 blockade in patients with advanced MMR-deficient cancers across 12 different types.  Objective radiographic responses were observed in 53% of patients and complete responses were achieved in 21% of patients.  Responses were durable with median progression-free and overall survival still not reached.  Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor.  These data support the hypothesis that the very large number of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.","prettyUrl":"diaz-2017-science","following":false,"created":"06/01/2017","featured":false,"publishedDate":"06/01/2017","urlOrId":"diaz-2017-science","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1328e23c-50b4-471c-804d-045498ea58df","title":"Absence of functional fetal regulatory T cells in humans causes in utero organ-specific autoimmunity","investigator":"Allenspach, Eric J","investigatorInstitution":"University of Washington School of Medicine and Seattle Children's Research Institute","publicationName":"Journal of Allergy and Clinical Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"55":"allenspach-2017-jallergyclinimmunol"},"prettyUrlList":["allenspach-2017-jallergyclinimmunol"],"summary":"Fetal T regulatory (Treg) cells are present by 13 weeks gestation, but their role during the fetal period is unclear. Maternal Treg cells clearly are critical for fetal tolerance. Human fetal Treg cells promote tolerance to noninherited maternal antigens in utero, but whether tissue-specific self-tolerance is needed in utero is unknown. During pregnancy, fetuses with the genetic disorder Immune dysregulation Polyendocrinopathy Enteropathy X- linked (IPEX) syndrome lack functional Treg cells, but maternal Treg cells remain functional. Patients with IPEX syndrome often appear healthy at birth, but develop early systemic autoimmunity including early-onset diabetes, enteropathy, thyroiditis, and dermatitis. Timing of the initial organ-specific inflammation remains unclear. Early fetal or perinatal IPEX presentations are reported, but evidence for in utero organ-specific autoimmunity is lacking. In this study, we report 2 patients with IPEX syndrome who died shortly after birth with histological evidence for tertiary lymphoid structures, chronic inflammatory changes, and targeted exocrine pancreas autoimmunity in the absence of clinical diabetes. Repertoire analysis demonstrated clonal enrichment within the pancreas consistent with an antigen-driven germinal center reaction. A murine model with inducible inactivation of Treg cells demonstrated similar exocrine-dominant lymphocytic infiltrates in the pancreas. Thus, absence of functional Treg cells promotes organ-specific, exocrine pancreas autoimmunity in utero.","prettyUrl":"allenspach-2017-jallergyclinimmunol","following":false,"created":"05/17/2017","featured":false,"publishedDate":"05/22/2017","urlOrId":"allenspach-2017-jallergyclinimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"e19cf008-6363-4bd7-8f75-05bc29e17600","title":"Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis","investigator":"Mustjoki, Satu","investigatorInstitution":"Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center","publicationName":"Nature Communications","researchArea":"RA","prettyUrls":{"58":"mustjoki-2017-natcomms"},"prettyUrlList":["mustjoki-2017-natcomms"],"summary":"Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.","prettyUrl":"mustjoki-2017-natcomms","following":false,"created":"04/26/2017","featured":false,"publishedDate":"05/04/2017","urlOrId":"mustjoki-2017-natcomms","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"30401d58-e395-4f98-867b-2b2e0dd19712","title":"Broad TCR repertoire and diverse structural solutions for recognition of an immunodominant CD8+ T cell epitope","investigator":"Selin, Liisa K.","investigatorInstitution":"University of Massachusetts Medical School","publicationName":"Nature Structural and Molecular Biology","researchArea":"Basic Immunology","prettyUrls":{"54":"stern-2017-natstructmolbio"},"prettyUrlList":["stern-2017-natstructmolbio"],"summary":"A keystone of antiviral immunity is CD8 T-cell recognition of viral peptides bound to MHC-I proteins. The recognition mode of individual T cell receptors (TCRs) has been studied in some detail, but the extent of TCR variation in the response to a viral antigen is unclear. The influenza M1 epitope is an immunodominant target of CD8 T cells helping to control influenza in HLA-A2+ individuals. Here, we show that thousands of different TCRs are used by CD8 T cells to recognize HLA-A2/M1, encoding different structural solutions to the problem of specifically recognizing a relatively featureless peptide antigen previously thought to greatly constrain TCR selection. The vast majority of responding TCRs targets a small cleft between the peptide and MHC. These broad repertoires lead to plasticity in antigen recognition and protection against T cell clonal loss and viral escape.","prettyUrl":"stern-2017-natstructmolbio","following":false,"created":"04/12/2017","featured":false,"publishedDate":"04/12/2017","urlOrId":"stern-2017-natstructmolbio","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d30421c5-7d60-46d2-bcc9-665f3b7eba79","title":"Mouse IgH strain comparison","investigator":"Hamm, David","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Basic Immunology","prettyUrls":{"53":"mouse-igh-control"},"prettyUrlList":["mouse-igh-control"],"summary":"This is Adaptive generated control data looking at matched mesenteric lymph node, spleen and for one strain, bone marrow. There are three 8-week-old mice per strain (C57Bl/6, BalbC and CD1) acquired from Charles River.","prettyUrl":"mouse-igh-control","following":false,"created":"03/13/2017","featured":false,"publishedDate":"04/06/2017","urlOrId":"mouse-igh-control","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"54ac32ec-6500-45ea-8efa-6fd109a1cf7e","title":"The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma","investigator":"Gandhi, Maher","investigatorInstitution":"Leukaemia Foundation of Queensland Blood Cancer Research Laboratory, University of Queensland Diamantina Institute, Translational Research Institute","publicationName":"Clin Cancer Res","researchArea":"Cancer","prettyUrls":{"52":"keane-2016-clincancerres"},"prettyUrlList":["keane-2016-clincancerres"],"summary":"Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo Diffuse Large B-cell Lymphoma (DLBCL), and the TCR’s impact on survival. Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population based cohort of 92 DLBCL patients treated with conventional (i.e. non-checkpoint blockade) frontline ‘R-CHOP’ therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString(TM). The primary endpoints were 4-year overall and progression free survival (OS and PFS).\n\nResults: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (p<0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS of 60.0% (95% C.I. 31.7-79.6%), compared to 79.8% in patients with a low dominant clone (95% C.I. 66.7-88.5%, p=0.005). A highly dominant clone also predicted inferior 4-year PFS of 46.6% (95% C.I. 22.5-76.6%) versus 72.6% (95% C.I. 58.8-82.4%, p=0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1 and PD-L2 immune checkpoint molecules.\n\nConclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.","prettyUrl":"keane-2016-clincancerres","following":false,"created":"04/05/2017","featured":false,"publishedDate":"04/05/2017","urlOrId":"keane-2016-clincancerres","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3a2ffef9-9bf6-486f-aa68-fa8c92893c5e","title":"Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells","investigator":"Herati, Ramin","investigatorInstitution":"University of Pennsylvania Perelman School of Medicine","publicationName":"Science Immunology","researchArea":"Vaccine efficacy","prettyUrls":{"51":"herati-2017-sciimmunol"},"prettyUrlList":["herati-2017-sciimmunol"],"summary":"T follicular helper (TFH) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTFH, have similarity to lymphoid TFH, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTFH respond in an antigen-specific manner and whether they form long-lasting memory. We identified a cTFH population that expressed multiple T cell activation markers and could be readily identified by coexpression of inducible costimulator (ICOS) and CD38. This subset expressed more Bcl6, c-Maf, and interleukin-21 than did other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS+CD38+ cTFH at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated activation-induced marker expression. Moreover, T cell receptor β chain sequencing identified a clonal response in ICOS+CD38+ cTFH that strongly correlated with the increased cTFH frequency and was associated with the circulating plasmablast response. In participants who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS+CD38+ cTFH subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTFH after vaccination persisted in the ICOS−CD38− cTFH repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more stable ICOS−CD38− cTFH subset. These data highlight the antigen specificity, lineage relationships, and memory properties of human cTFH responses to vaccination, providing new avenues for tracking and monitoring cTFH responses during infection and vaccination in humans.","prettyUrl":"herati-2017-sciimmunol","following":false,"created":"04/05/2017","featured":false,"publishedDate":"04/05/2017","urlOrId":"herati-2017-sciimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5dd7b508-079b-4cf6-872d-4a91e5e3e5db","title":"Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T-cell repertoire","investigator":"Harlan Robins","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Nature Genetics","researchArea":"Infectious Disease","prettyUrls":{"49":"emerson-2017-natgen"},"prettyUrlList":["emerson-2017-natgen"],"summary":"An individual’s T-cell repertoire dynamically encodes their pathogen exposure history. To determine if specific pathogen exposure signatures can be identified by documenting public TCRs, we profiled the T-cell repertoire of 666 subjects with known cytomegalovirus (CMV) serostatus by immunosequencing, and we developed a statistical classification framework that can diagnose CMV status from the resulting catalog of TCRb sequences with high specificity and sensitivity, both in the original cohort and in an independent validation cohort of 120 subjects.  We confirmed that 3 of the identified CMV-associated TCRb bind CMV in vitro, and furthermore we used this approach to accurately predict the HLA-A and –B alleles of most subjects in the first cohort. Since all memory T-cell responses are encoded in the common format of somatic TCR recombination, our approach could potentially be generalized to a wide variety of disease states, as well as other immunological phenotypes as a highly parallelizable diagnostic strategy. <a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/emerson-2017-natgen/emerson-2017-natgen.zip\">Download full data set (18.53GB)</a>.","prettyUrl":"emerson-2017-natgen","following":false,"created":"09/15/2016","featured":false,"publishedDate":"02/27/2017","urlOrId":"emerson-2017-natgen","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"15637699-82f7-4d01-80f4-cd08f280279f","title":"CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin","investigator":"Eidsmo, Liv","investigatorInstitution":"Department of Medicine, Solna","publicationName":"Cell Immunity","researchArea":"Dermatology","prettyUrls":{"46":"cheuk-2017-immunity"},"prettyUrlList":["cheuk-2017-immunity"],"summary":"Immunoseq analysis on TCRB were performed on epidermal and dermal CD8+ T cells from healthy skin sorted according to their surface expression of CD103 and CD49a (n=5). Circulating CD62L-CD45RA- effector memory cells from the same donors were also analysed for comparison.","prettyUrl":"cheuk-2017-immunity","following":false,"created":"01/18/2017","featured":false,"publishedDate":"02/15/2017","urlOrId":"cheuk-2017-immunity","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"48160fb8-2650-44ec-8a06-a85db98b1fca","title":"Neutrophils dominate the immune cell composition in non-small cell lung cancer","investigator":"Kargl, Julia","investigatorInstitution":"Clinical Research Division","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"48":"houghton-2017-ncomms"},"prettyUrlList":["houghton-2017-ncomms"],"summary":"The response rate to immune checkpoint inhibitor therapy for non-small cell lung cancer (NSCLC) is just 20%. To improve upon this figure, a number of early phase clinical trials employing novel immunotherapeutics in conjunction with immune checkpoint blockade have been initiated. Unfortunately, these trials have been designed without a strong foundational knowledge of the immune landscape present in NSCLC. Here, we use a flow cytometry panel capable of measuring 51 immune cell populations to comprehensively identify the immune cell composition and function in NSCLC. The results show that the immune cell composition is fundamentally different in lung adenocarcinoma as compared to lung squamous cell carcinoma, and that neutrophils are the most prevalent immune cell type. Using a combination of T cell receptor-ß sequencing and tumor reactivity assays, we also predict that tumor-reactive T cells are frequently present in NSCLC. These results should help to guide both the design of clinical trials and the direction of future research in this area.","prettyUrl":"houghton-2017-ncomms","following":false,"created":"02/14/2017","featured":false,"publishedDate":"02/14/2017","urlOrId":"houghton-2017-ncomms","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b2bc098c-da25-4e98-80d1-161f59d856e0","title":"High-Throughput Sequencing of the B Cell Receptor in African Burkitt Lymphoma Reveals Clues to Pathogenesis","investigator":"Warren, Edus","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Blood Advances","researchArea":"Cancer","prettyUrls":{"47":"lombardo-2017-bloodadvances"},"prettyUrlList":["lombardo-2017-bloodadvances"],"summary":"Burkitt lymphoma (BL), the most common pediatric cancer in sub-Saharan Africa, is a malignancy of antigen-experienced B-lymphocytes. High-throughput sequencing (HTS) of the immunoglobulin heavy (IGH) and light chain (IGK/IGL) loci was performed on genomic DNA from 51 primary BL tumors: 19 from Uganda and 32 from Ghana. RT-PCR analysis and sequencing of tumor RNA (RNAseq) was performed on the Ugandan tumors to confirm and extend the findings from HTS of tumor DNA. Clonal IGH and IGK/IGL rearrangements were identified in 41 and 46 tumors, respectively. Evidence for rearrangement of the second IGH allele was observed in only 6 of 41 tumor samples with a clonal IGH rearrangement, suggesting that the normal process of biallelic IGHD to IGHJ (DJ) rearrangement is often disrupted in BL progenitor cells.  Most tumors, including those with a sole dominant non-expressed DJ rearrangement, contained many IGH and IGK/IGL sequences that differed from the dominant rearrangement by <10 nucleotides, suggesting that the target of ongoing mutagenesis of these loci in BL tumor cells is not limited to expressed alleles. IGHV usage in both BL tumor cohorts revealed enrichment for IGHV genes that are infrequently utilized in memory B-cells from healthy subjects. Analysis of publicly available DNA sequencing and RNAseq data revealed that these same IGHV genes were over-represented in dominant tumor-associated IGH rearrangements in several independent BL tumor cohorts. These data suggest that BL derives from an abnormal B-cell progenitor and that aberrant mutational processes are active on the immunoglobulin loci in BL cells.","prettyUrl":"lombardo-2017-bloodadvances","following":false,"created":"02/03/2017","featured":false,"publishedDate":"02/07/2017","urlOrId":"lombardo-2017-bloodadvances","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3d047774-29d9-441f-a71e-7725b5891b4d","title":"TCRB technical replicates of PBMC from four donors","investigator":"Gil, Julie","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Controls","prettyUrls":{"118":"tcrb-technical-replicates"},"prettyUrlList":["tcrb-technical-replicates"],"summary":"Peripheral blood mononuclear cell (PBMC) samples were taken from four healthy adults.  For two of the subjects, T cells were sorted out prior to DNA extraction.  gDNA was extracted from each subject's sample and was divided into ~40 aliquots per subject.  The ~40 aliquots were run on either the immunoSEQ TCRB Assay service or Kit. The kit samples were run on multiple flow cells and at multiple locations.  Samples from subjects 1-3 were run as deeps (6 wells).  Samples from subject 4 were run as surveys (2 wells).  Subject 4 samples are known to be more clonal than the other samples.","prettyUrl":"tcrb-technical-replicates","following":false,"created":"01/03/2017","featured":false,"publishedDate":"01/30/2017","urlOrId":"tcrb-technical-replicates","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9447534e-f086-484e-b66a-2e6a05561a1a","title":"Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy","investigator":"Page, David B.","investigatorInstitution":"Providence Portland / Robert W. Franz Cancer Research Center and Earl A. Chiles Research Institute","publicationName":"Cancer Immunology Research 2016 Oct;4(10):835-844","researchArea":"Cancer Immunotherapy","prettyUrls":{"45":"page-2016-cir"},"prettyUrlList":["page-2016-cir"],"summary":"In early stage breast cancer, the degree of tumor-infiltrating lymphocytes (TILs) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryo-immunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated pre- operatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 x 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared to monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring, and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T cell responses to therapy and for the study of cryo-immunotherapy in early-stage breast cancer.","prettyUrl":"page-2016-cir","following":false,"created":"01/21/2017","featured":false,"publishedDate":"01/24/2017","urlOrId":"page-2016-cir","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"57d66e54-19d1-4f15-83ea-df473355e2e4","title":"Selective Expansion of High Functional Avidity Memory CD8 T Cell Clonotypes During Hepatitis C Virus Reinfection and Clearance","investigator":"Shoukry, Naglaa","investigatorInstitution":"Centre de Recherche du Centre Hospitalier de l’Université de Montréal","publicationName":"PLoS Pathogens","researchArea":"Infectious Disease","prettyUrls":{"44":"shoukry-2017-plospathogens"},"prettyUrlList":["shoukry-2017-plospathogens"],"summary":"The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before, during and after hepatitis C virus (HCV) reinfection in patients who spontaneously resolved two consecutive infections (SR/SR) and patients who resolved a primary but failed to clear a subsequent infection (SR/CI). The TCR repertoire was narrower prior to reinfection in the SR/SR group as compared to the SR/CI group and became more focused upon reinfection. CD8 T cell clonotypes expanding upon re-exposure and associated with protection from viral persistence were recruited from the memory T cell pool. Individual CD8 T cell clones generated from the SR/SR group exhibited higher functional avidity and polyfunctionality as compared to clones from the SR/CI group. Our results suggest that protection from viral persistence upon HCV reinfection is associated with focusing of the HCV-specific CD8 memory T cell repertoire whereby clonotypes with the highest functional avidity are selected. These findings are applicable to vaccination strategies aiming at shaping the protective human T cell repertoire.","prettyUrl":"shoukry-2017-plospathogens","following":false,"created":"12/05/2016","featured":false,"publishedDate":"01/20/2017","urlOrId":"shoukry-2017-plospathogens","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"45ead042-9a68-4e11-b53f-3b84ef44be46","title":"Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities","investigator":"Sharma, Padmanee","investigatorInstitution":"Department of Genitourinary Medical Oncology","publicationName":"PNAS","researchArea":"Cancer Immunotherapy","prettyUrls":{"39":"sharma-2016-pnas"},"prettyUrlList":["sharma-2016-pnas"],"summary":"Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently lacking. In a phase II clinical trial that treated 27 patients with metastatic prostate cancer, we aimed to test the safety and efficacy of androgen deprivation therapy plus ipilimumab. In this study, we observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor β-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2–3 irAEs. These initial results suggested that expansion of ≥55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2–3 irAEs also had expansion of ≥55 CD8 T-cell clones in blood samples collected before the onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.","prettyUrl":"sharma-2016-pnas","following":false,"created":"10/24/2016","featured":false,"publishedDate":"12/19/2016","urlOrId":"sharma-2016-pnas","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b4fa7805-9e3a-4273-b33c-962442be5e9d","title":"Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes","investigator":"Brusko, Todd","investigatorInstitution":"Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida","publicationName":"JCI Insight","researchArea":"Autoimmune Disorders","prettyUrls":{"41":"seay-2016-jciinsight"},"prettyUrlList":["seay-2016-jciinsight"],"summary":"The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic-draining lymph nodes (pLN), “irrelevant” non-pancreatic-draining lymph nodes (iLN), peripheral blood mononuclear cells (PBMC), and splenocytes from T1D (N=18) and control donors (N=9), as well as pancreatic islets of one T1D patient, and from these tissues, purified CD4+ conventional T cells (Tconv), CD4+ regulatory T cells (Treg), CD8+ T cells, and B cells. By conducting high-throughput immunosequencing of the T cell receptor (TCR) -chain (TRB) and B cell receptor (BCR) immunoglobulin heavy chain (IGH) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4+ repertoire, while up to 24% of CD8+ clones were shared among tissues. We surveyed our dataset for previously described proinsulin- and glutamic acid decarboxylase 65 (GAD65)-reactive receptors, and interestingly, we observed a TRB with homology to a known GAD65-reactive TCR (clone GAD4.13) present in seven T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of one T1D subject. These data demonstrate diverse TCR signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors.","prettyUrl":"seay-2016-jciinsight","following":false,"created":"12/05/2016","featured":false,"publishedDate":"12/07/2016","urlOrId":"seay-2016-jciinsight","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2e838d8c-99cb-4103-b79e-7ee32768536d","title":"Long-term maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites","investigator":"Donna L. Farber","investigatorInstitution":"Columbia University in the City of New York","publicationName":"Science Immunology","researchArea":"Basic Immunology","prettyUrls":{"40":"farber-2016-sciimmunol"},"prettyUrlList":["farber-2016-sciimmunol"],"summary":"Naïve T cells develop in the thymus and coordinate immune responses to new antigens; however, mechanisms for their long-term persistence over the human lifespan remain undefined.  Here, we investigated human naïve T cell development and maintenance in primary and secondary lymphoid tissues obtained from individual organ donors aged 3 months-73 years. In the thymus, the frequency of double-positive thymocytes declined sharply in donors over age 40 coincident with reduced recent thymic emigrants (RTE) in lymphoid tissues, while naïve T cells were functionally maintained predominantly in lymph nodes (LN).  Analysis of TCR clonal distribution by CDR3 sequencing of naïve CD4+ and CD8+ T cells in spleen and LNs reveal site-specific clonal expansions of naïve T cells from individuals >40 years of age with minimal clonal overlap between lymphoid tissues.  We also identified biased naïve T cell clonal distribution within specific lymph nodes based on VJ usage. Together these results suggest prolonged maintenance of naïve T cells through in situ homeostasis and retention in lymphoid tissue.","prettyUrl":"farber-2016-sciimmunol","following":false,"created":"11/18/2016","featured":false,"publishedDate":"12/05/2016","urlOrId":"farber-2016-sciimmunol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b5a09b72-edb0-49fa-bfa1-560a8b0b5bbe","title":"T cells from mouse C57BL/6 skin: 3 wild types and 1 OTII mouse","investigator":"Koralov, Sergei","investigatorInstitution":"Department of Pathology","publicationName":"","researchArea":"Controls","prettyUrls":{"116":"mouse-skin-2016"},"prettyUrlList":["mouse-skin-2016"],"summary":"OT II mice express a TCRA/B receptor that pairs with the CD4 coreceptor and is specific for avian (chicken) ovalbumin 323-339 in the context. There is a four-fold increase in the CD4 to CD8 peripheral T cell ratio in these mice, and lymph node T cells demonstrate a dose-dependent proliferative response to the specific ovalbumin ligand. They are often used in T-cell biology research.","prettyUrl":"mouse-skin-2016","following":false,"created":"12/01/2016","featured":false,"publishedDate":"12/01/2016","urlOrId":"mouse-skin-2016","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3163f96d-8209-435d-8551-c33d453667bf","title":"Novel E2 glycoprotein tetramer detects HCV-specific memory B cells","investigator":"Shoukry, Naglaa and Grakoui, Arash","investigatorInstitution":"Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM),  Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine; Yerkes National Primate Research Center, Emory Vaccine Center","publicationName":"Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"37":"boisvert-2016-ji"},"prettyUrlList":["boisvert-2016-ji"],"summary":"Acute hepatitis C virus (HCV) infection culminates in viral persistence in the majority of cases. Antibodies that recognize the envelope glycoproteins E1 and E2 are generated during the late stages of acute infection, yet their contribution to spontaneous viral clearance remains 1:21 Investigation of the humoral responses during acute HCV infection have been limited by the inability to directly identify and characterize HCV-specific B cells. Here we describe the development of a novel tetramer of the E2 glycoprotein ectodomain (J6, genotype 2a strain), which allowed us to visualize E2-specific B cells longitudinally in the peripheral blood of HCV-infected individuals. HCV-specific class-switched memory B cells were detected in 3/7 participants during late acute infection, with a mean frequency of 0.63% for positive samples (range: 0.16 to 0.67) and in 7/7 participants with chronic infection with a mean frequency of 0.47% (range: 0.20% to 0.78%). In a cross-sectional study, E2 tetramer positive population was detected in 28/31 chronically infected individuals. Deep sequencing of the B cell receptor (BCR) from E2-specific class-switched memory B cells sorted from two independent participants revealed a focused repertoire suggestive of clonal selection. Tetramer-specific B cells exhibited skewed CDR3 length distribution and increased mutation frequency compared to naive B cells. This BCR profile is indicative of clonal expansion and affinity maturation. E2 tetramer allows for specific and sensitive ex vivo characterization of rare HCV-specific B cells in infected individuals, and will enable researchers to gain a better understanding of humoral immunity in HCV infection.","prettyUrl":"boisvert-2016-ji","following":false,"created":"09/29/2016","featured":false,"publishedDate":"09/29/2016","urlOrId":"boisvert-2016-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"5eaca36e-c0b9-4be5-aeaa-bc1d230af791","title":"Estimating the ratio of CD4+ to CD8+ T cells using high-throughput sequence data","investigator":"Robins, Harlan","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"Journal of Immunological Methods","researchArea":"Basic Immunology","prettyUrls":{"36":"emerson-2013-jim"},"prettyUrlList":["emerson-2013-jim"],"summary":"Mature T cells express either CD8 or CD4, defining two physiologically distinct populations of T cells. CD8+ T cells, or killer T-cells, and CD4+ T cells, or helper T cells, effect different aspects of T cell mediated adaptive immunity. Currently, determining the ratio of CD4+ to CD8+ T cells requires flow cytometry or immunohistochemistry. The genomic T cell receptor locus is rearranged during T cell maturation, generating a highly variable T cell receptor locus in each mature T cell. As part of thymic maturation, T cells that will become CD4+ versus CD8+ are subjected to different selective pressures. In this study, we apply high-throughput next-generation sequencing to T cells from both a healthy cohort and a cohort with an autoimmune disease (multiple sclerosis) to identify sequence features in the variable CDR3 region of the rearranged T cell receptor gene that distinguish CD4+ from CD8+ T cells. We identify sequence features that differ between CD4+ and CD8+ T cells, including Variable gene usage and CDR3 region length. We implement a likelihood model to estimate relative proportions of CD4+ and CD8+ T cells using these features. Our model accurately estimates the proportion of CD4+ and CD8+ T cell sequences in samples from healthy and diseased immune systems, and simulations indicate that it can be applied to as few as 1000 T cell receptor sequences; we validate this model using in vitro mixtures of T cell sequences, and by comparing the results of our method to flow cytometry using peripheral blood samples. We believe our computational method for determining the CD4:CD8 ratio in T cell samples from sequence data will provide additional useful information for any samples on which high-throughput TCR sequencing is performed, potentially including some solid tumors.","prettyUrl":"emerson-2013-jim","following":false,"created":"09/21/2016","featured":false,"publishedDate":"09/21/2016","urlOrId":"emerson-2013-jim","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f0d23845-f15b-49c8-9044-f3f44b392e5a","title":"Atezolizumab in combination with bevacizumab enhances migration of antigen-specific T-cells in metastatic renal cell carcinoma","investigator":"Wallin, Jeffrey","investigatorInstitution":"Genentech Inc.","publicationName":"Nature Communications","researchArea":"Cancer Immunotherapy","prettyUrls":{"32":"Wallin-2016-NatureCom"},"prettyUrlList":["Wallin-2016-NatureCom"],"summary":"Anti-tumor immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients.  In preclinical models tumor-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation.  This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC.  Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab.  We discover that intra-tumoral CD8+ T-cells increase following combination treatment.  A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine).  We also discover that the fractalkine receptor increases on peripheral CD8+ T-cells with treatment.  Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment.  These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.","prettyUrl":"Wallin-2016-NatureCom","following":false,"created":"09/06/2016","featured":false,"publishedDate":"09/06/2016","urlOrId":"Wallin-2016-NatureCom","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"1c7ce2e3-808e-44da-b1e9-c44914719828","title":"A public database of memory and naive B-cell receptor sequences","investigator":"Robins, Harlan","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"PLOS ONE","researchArea":"Basic Immunology","prettyUrls":{"8":"robins-bcell-2016"},"prettyUrlList":["robins-bcell-2016"],"summary":"The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics.\n\nSince this dataset is very large, to download the underlying data please go to:\nhttps://s3-us-west-2.amazonaws.com/publishedproject-supplements/brr/public-bcell-dataset.tgz for a zipped file.","prettyUrl":"robins-bcell-2016","following":false,"created":"08/12/2016","featured":false,"publishedDate":"08/12/2016","urlOrId":"robins-bcell-2016","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"9816555b-5673-4316-85e2-244acb293f0b","title":"Efficient Culture of Human Naïve and Memory B cells for Use as Antigen-presenting Cells","investigator":"Kelsoe, Garnett","investigatorInstitution":"Duke University","publicationName":"The Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"117":"kelsoe-2016-ji"},"prettyUrlList":["kelsoe-2016-ji"],"summary":"The ability to culture and expand B cells in vitro has become a useful tool for studying human immunity. A limitation of current methods for human B-cell culture is the capacity to support mature B-cell proliferation. We have developed a culture method to support the efficient activation and proliferation of both naïve and memory human B cells. This culture supports extensive B-cell proliferation, with approximately 103-fold increases following 8 days in culture, and 106-fold increases when cultures are split and cultured for 8 more days. The capacity for continued proliferation is stable for at least another week. In culture, a significant fraction of naïve B cells undergo isotype switching and differentiate into plasmacytes. Culture-derived (CD) B cells are readily cryopreserved, and when recovered, retain their ability to proliferate and differentiate. Significantly, proliferating CD B cells express high levels of MHCII, CD80, and CD86. CD B cells act as APCs and present both alloantigens and microbial antigens to T cells. We are able to activate and expand antigen-specific memory B cells; these cultured cells are highly effective in presenting antigen to T cells. With CD culture method, we have characterized TCR repertoire for tetanus toxoid (TT)-reactive T cells; we have obtained >8,000 rearranged TCRB genes from TT-reactive CD4+ T cells and found that while biased Vbeta representation features TT-activated T cells within an individual, Vbeta use of TT-activated T cells differs between unrelated individuals. This culture method provides a platform for studying the BCR and TCR repertoires within a single individual.","prettyUrl":"kelsoe-2016-ji","following":false,"created":"08/08/2016","featured":false,"publishedDate":"08/08/2016","urlOrId":"kelsoe-2016-ji","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a322cfd8-b842-4544-8004-4249fd5cefa7","title":"TCR Sequencing Can Identify and Track Glioma- Infiltrating T Cells after DC Vaccination","investigator":"Prins, Robert","investigatorInstitution":"Department of Neurosurgery, David Geffen School of Medicine","publicationName":"Cancer Immunology Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"4":"Prins-2016-Cancerimmunolres"},"prettyUrlList":["Prins-2016-Cancerimmunolres"],"summary":"Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate–pulsed dendritic\ncell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the\nsuccessful, antigen-specific immune response.","prettyUrl":"Prins-2016-Cancerimmunolres","following":false,"created":"07/05/2016","featured":false,"publishedDate":"07/05/2016","urlOrId":"Prins-2016-Cancerimmunolres","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"73f41314-41d0-4958-ad11-b315c45ffa5a","title":"TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis","investigator":"Rossetti, Maura","investigatorInstitution":"University of California, Los Angeles","publicationName":"Annals of the Rheumatic Diseases","researchArea":"Autoimmune Disorders","prettyUrls":{"15":"Rossetti-2015-annrheumdis"},"prettyUrlList":["Rossetti-2015-annrheumdis"],"summary":"Objectives. The imbalance between effector and regulatory T (Treg) cells is crucial in the pathogenesis of autoimmune arthritis. Immune responses are often investigated in the blood because of its accessibility, but circulating lymphocytes are not representative of those found in inflamed tissues. This disconnect hinders our understanding of the mechanisms underlying disease. Our goal was to identify Treg cells implicated in autoimmunity at the inflamed joints, but also readily detectable in the blood upon recirculation.\nMethods. We compared Treg cells of JIA patients responding or not to therapy by using: (i) TCR sequencing, to identify clonotypes shared between blood and synovial fluid; (ii) FOXP3 TSDR DNA methylation assays, to investigate their stability; and (iii) flow cytometry and suppression assays to probe their tolerogenic functions.\nResults. We found a subset of synovial Treg cells that recirculated into the bloodstream of juvenile idiopathic and adult rheumatoid arthritis patients. These inflammation-associated (ia)Treg cells, but not other blood Treg cells, expanded during active disease and proliferated in response to their cognate antigens. Despite the typical inflammatory-skewed balance of immune mechanisms in arthritis, iaTreg cells were stably committed to the regulatory lineage and fully suppressive. A fraction of iaTreg clonotypes were in common with pathogenic effector T cells.\nConclusions. Using an innovative antigen-agnostic approach, we uncovered a population of bona fide synovial Treg cells readily accessible from the blood and selectively expanding during active disease, paving the way to non-invasive diagnostics and better understanding of the pathogenesis of autoimmunity.","prettyUrl":"Rossetti-2015-annrheumdis","following":false,"created":"05/24/2016","featured":false,"publishedDate":"06/03/2016","urlOrId":"Rossetti-2015-annrheumdis","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"bbfe9cc7-2917-424d-9ead-217b674ea17a","title":"Landscape of tumor-infiltrating T cell repertoire of human cancers","investigator":"Liu, X. Shirley","investigatorInstitution":"Department of Biostatistics and Computational Biology","publicationName":"Nature Genetics","researchArea":"Cancer Immunotherapy","prettyUrls":{"31":"Liu-2016-NatGenetics"},"prettyUrlList":["Liu-2016-NatGenetics"],"summary":"We developed a computational method to infer the complementarity determining region 3 (CDR3) sequences of tumor infiltrating T-cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600 thousand CDR3 sequences, including 15% with full-length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage of infiltrating T-cells in many tumors, except brain and kidney cancers, resembled those in the peripheral blood of healthy donors. We observed a strong association between T-cell diversity and tumor mutation load, and predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified 3 potential immunogenic somatic mutations based on their co-occurrence with CDR3 sequences. One of them, PRAMEF4 F300V, was predicted to bind strongly to both MHC-I and MHC-II, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and the tumor-reactive T-cell clonotypes.","prettyUrl":"Liu-2016-NatGenetics","following":false,"created":"04/26/2016","featured":false,"publishedDate":"04/28/2016","urlOrId":"Liu-2016-NatGenetics","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c1a5b132-cd91-44c6-ad66-3c6aab65fb52","title":"Origin and evolution of the T-cell repertoire after posttransplantation cyclophosphamide","investigator":"Warren, EH","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"JCI Insight","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"30":"Kanakry-2016-JCIInsight"},"prettyUrlList":["Kanakry-2016-JCIInsight"],"summary":"Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n=74) and antigen receptor sequencing (n=35) in recipients of myeloablative, HLA-matched allogeneic bone marrow transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower TRB repertoire diversity than input donor repertoires. Recovering B cells were predominantly naïve with IGH repertoire diversity similar to donors. Numerical T-cell reconstitution and TRB diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1-2 months posttransplant, but increased over the balance of the first posttransplant year. Blood TRB repertoires at ≥3 months posttransplant were often dominated by clones present in the donor blood/marrow memory CD8+ compartment. Limited overlap was observed between the TRB repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public TRB sequences associated with herpesvirus- or alloantigen-specific CD8+ T cells were detected in some patients, posttransplant TRB and IGH repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared.","prettyUrl":"Kanakry-2016-JCIInsight","following":false,"created":"04/18/2016","featured":false,"publishedDate":"04/20/2016","urlOrId":"Kanakry-2016-JCIInsight","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b9a2b206-7062-4900-a93a-b84eb5b01fdf","title":"The evolution of thymic lymphomas in p53 knockout mice","investigator":"Levine, Arnold","investigatorInstitution":"Institute for Advanced Study","publicationName":"Genes & Development","researchArea":"Cancer","prettyUrls":{"9":"Dudgeon-2014-GenesDev"},"prettyUrlList":["Dudgeon-2014-GenesDev"],"summary":"Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors’ driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.","prettyUrl":"Dudgeon-2014-GenesDev","following":false,"created":"03/24/2016","featured":false,"publishedDate":"04/15/2016","urlOrId":"Dudgeon-2014-GenesDev","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"26850bab-517f-4893-9261-38798cb71bbb","title":"A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells.","investigator":"Iijima, Norifumi","investigatorInstitution":"Department of Immunobiology, Yale University School of Medicine","publicationName":"Science","researchArea":"Infectious Disease","prettyUrls":{"16":"Iijima-2014-Science"},"prettyUrlList":["Iijima-2014-Science"],"summary":"CD8 tissue-resident memory T (T(RM)) cells provide efficient local control of viral infection, but the role of CD4 T(RM) is less clear. Here, by using parabiotic mice, we show that a preexisting pool of CD4 T(RM) cells in the genital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. Chemokines secreted by a local network of macrophages maintained vaginal CD4 T(RM) in memory lymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 T(RM) cells within the MLCs were enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccine strategies that enable establishment of T(RM) cells for protection from a sexually transmitted virus and provide insights as to how such a pool might be established.","prettyUrl":"Iijima-2014-Science","following":false,"created":"12/04/2015","featured":false,"publishedDate":"01/27/2016","urlOrId":"Iijima-2014-Science","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"7cf42f6b-7c85-4ad2-98a7-7793787574da","title":"Rapid evolution of the CD8+ T cell receptor repertoire in neonatal mice","investigator":"Carey, Alison","investigatorInstitution":"Drexel University College of Medicine","publicationName":"Journal of Immunology","researchArea":"Basic Immunology","prettyUrls":{"11":"Carey-2016-JI"},"prettyUrlList":["Carey-2016-JI"],"summary":"Currently, there is little consensus regarding the most appropriate animal model to study acute infection and the virus–specific CD8+ T cell (CTL) responses in neonates.  TCRβ high-throughput sequencing in naïve CTL of differently aged neonatal mice was performed, which demonstrated differential Vβ family gene usage.  Using an acute influenza infection model, we examined the TCR repertoire of the CTL response in neonatal and adult mice infected with influenza type A virus. Three-day old mice mounted a greatly reduced primary NP(366-374)-specific CTL response when compared to 7-day old and adult mice, while secondary CTL responses were normal. Analysis of NP(366-374)-specific CTL TCR repertoire revealed different Vβ gene usage and an absence of public clonotypes in 3-day old neonates.  This could underlie the impaired CTL response in these neonates.","prettyUrl":"Carey-2016-JI","following":false,"created":"11/17/2015","featured":false,"publishedDate":"01/15/2016","urlOrId":"Carey-2016-JI","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"14e9bfaa-9ef6-469d-985b-be8629b6a562","title":"Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection","investigator":"Zhu, J","investigatorInstitution":"Department of Laboratory Medicine","publicationName":"Nature","researchArea":"Infectious Disease","prettyUrls":{"25":"Zhu-2013-Nature"},"prettyUrlList":["Zhu-2013-Nature"],"summary":"Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8(+) T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ)--the portal of neuronal release of reactivating virus--for prolonged time periods after herpes lesions are cleared. The phenotype and function of this persistent CD8(+) T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T-cell antigen receptor β-chain (TCRβ) genotyping on sequential genital skin biopsies, we show that CD8αα(+) T cells are the dominant resident population of DEJ CD8(+) T cells that persist at the site of previous HSV-2 reactivation. CD8αα(+) T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR β-chain repertoire reveals that the DEJ CD8αα(+) T cells are oligoclonal with diverse usage of TCR variable-β genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8αα(+) T cells. These studies indicate that DEJ CD8αα(+) T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα(+) T cells may be a critical component for developing effective vaccines against skin and mucosal infections.","prettyUrl":"Zhu-2013-Nature","following":false,"created":"12/11/2015","featured":false,"publishedDate":"12/14/2015","urlOrId":"Zhu-2013-Nature","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"fb019ec0-9897-4437-84c6-c47b53d293bd","title":"De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.","investigator":"Mattoo, Hamid","investigatorInstitution":"Ragon Institute of MGH, MIT and Harvard","publicationName":"Journal of Allergy and Clinical Immunology","researchArea":"Autoimmune Disorders","prettyUrls":{"5":"Mattoo-Mahajan-2013-JAlCI"},"prettyUrlList":["Mattoo-Mahajan-2013-JAlCI"],"summary":"BACKGROUND: IgG4-related disease (IgG4-RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG4-expressing plasma cells at disease sites.\n\nOBJECTIVE: The role of B cells and IgG4 antibodies in IgG4-RD pathogenesis is not well defined. We evaluated patients with IgG4-RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disease pathogenesis.\n\nMETHODS: B-cell populations from the peripheral blood of 84 patients with active IgG4-RD were analyzed by using flow cytometry. The repertoire of B-cell populations was analyzed in a subset of patients by using next-generation sequencing. Fourteen of these patients were longitudinally followed for 9 to 15 months after rituximab therapy.\n\nRESULTS: Numbers of CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts, which are largely IgG4(+), are increased in patients with active IgG4-RD. These expanded plasmablasts are oligoclonal and exhibit extensive somatic hypermutation, and their numbers decrease after rituximab-mediated B-cell depletion therapy; this loss correlates with disease remission. A subset of patients relapse after rituximab therapy, and circulating plasmablasts that re-emerge in these subjects are clonally distinct and exhibit enhanced somatic hypermutation. Cloning and expression of immunoglobulin heavy and light chain genes from expanded plasmablasts at the peak of disease reveals that disease-associated IgG4 antibodies are self-reactive.\n\nCONCLUSIONS: Clonally expanded CD19(+)CD27(+)CD20(-)CD38(hi) plasmablasts are a hallmark of active IgG4-RD. Enhanced somatic mutation in activated B cells and plasmablasts and emergence of distinct plasmablast clones on relapse indicate that the disease pathogenesis is linked to de novo recruitment of naive B cells into T cell-dependent responses by CD4(+) T cells, likely driving a self-reactive disease process.","prettyUrl":"Mattoo-Mahajan-2013-JAlCI","following":false,"created":"11/06/2015","featured":false,"publishedDate":"12/09/2015","urlOrId":"Mattoo-Mahajan-2013-JAlCI","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"f4af3728-8ca2-4bd3-af74-69e497e7a250","title":"Annotation of pseudogenic gene segments by massively parallel sequencing of rearranged lymphocyte receptor loci","investigator":"Harlan Robins","investigatorInstitution":"Fred Huchinson Cancer Research Center","publicationName":"Genome Medicine","researchArea":"Basic Immunology","prettyUrls":{"33":"Dean-2015-GenomeMed"},"prettyUrlList":["Dean-2015-GenomeMed"],"summary":"The adaptive immune system generates a remarkable range of antigen-specific T-cell receptors (TCRs), enabling the recognition of a diverse set of antigens. To generate this diversity, T-cells undergo somatic recombination of noncontiguous variable (V), diversity (D), and joining (J) gene segments, which collectively encode the Complementarity Determining Region (CRD) 3 of the TCRβ chain (or of V and J gene segments for the TCRα chain). Further diversity is achieved by deletion and non-templated insertion of nucleotides at the D-J and V-DJ (or V-J) junctions. Many of these gene segments are annotated as being non-functional due to defects in their primary sequence, the absence of motifs necessary for rearrangement, or chromosomal locations outside of the T cell receptor locus. \n \nWe sought to utilize a novel method, based on high-throughput sequencing of rearranged TCR genes in a large cohort of subjects, to evaluate the use of functional and non-functional alleles of T cell receptor gene segments. We amplified and sequenced genomic DNA from the peripheral blood of 587 healthy adults using a multiplexed PCR assay that targets the variable region of the rearranged TCRβ locus, and we determined the presence and the proportion of productive rearrangements for each TCRβ V gene segment in each subject. We then used this information to annotate the functional status of TCRβ V gene segments.\n \nThese data were generated from samples included in the following study: \nImmunosequencing reveals diagnostic signatures of chronic viral infection in T cell memory (2015) Ryan Emerson, William DeWitt, Marissa Vignali, Jenna Gravley, Cindy Desmarais, Christoper Carlson, John Hansen, Mark Rieder, Harlan Robins\n(http://biorxiv.org/content/early/2015/09/11/026567)\n\nSince this dataset is very large, instead of using the \"Export Data' button on the orange box to the right, to download the underlying data please go to:\n<a href=\"https://adaptivepublic.blob.core.windows.net/publishedproject-supplements/dean-2015-genomemed/dean-2015-genomemed.zip\">Download full data (12.74GB)</a> \n for a zipped file.","prettyUrl":"Dean-2015-GenomeMed","following":false,"created":"09/22/2015","featured":false,"publishedDate":"12/07/2015","urlOrId":"Dean-2015-GenomeMed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"26d0678b-0260-4df0-824f-0995a6d6ce81","title":"Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich Syndrome","investigator":"Rawlings, David J.","investigatorInstitution":"Center for Immunity and Immunotherapy","publicationName":"Journal of Experimental Medicine","researchArea":"Autoimmune Disorders","prettyUrls":{"7":"Kolhatkar-2015-JEM"},"prettyUrlList":["Kolhatkar-2015-JEM"],"summary":"Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)-deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling suggesting that these pathways might impact establishment of the mature, naïve BCR repertoire. To directly investigate this possibility, we evaluated naïve B cell specificity and composition in WASp-deficient mice and WAS subjects (n=12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low affinity, self-reactive specificities in murine marginal zone (MZ) and human naïve B cells. While negative selection mechanisms including deletion, anergy and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a mAb recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naïve mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell-intrinsic, BCR and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.","prettyUrl":"Kolhatkar-2015-JEM","following":false,"created":"09/23/2015","featured":false,"publishedDate":"10/26/2015","urlOrId":"Kolhatkar-2015-JEM","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"049723a4-eb6a-421d-be66-f382fa2c57dd","title":"A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment","investigator":"Albani, Salvatore","investigatorInstitution":"SingHealth Translational Immunology and Inflammation Centre, Singhealth and Duke-NUS Graduate Medical School","publicationName":"Annals of the Rheumatic Diseases","researchArea":"Autoimmune Disorders","prettyUrls":{"17":"Salvatore-2015-AnnRheuDis"},"prettyUrlList":["Salvatore-2015-AnnRheuDis"],"summary":"Objectives. Systemic immunological processes are profoundly shaped by the micro-environments where antigen recognition occurs. Identifying molecular signatures distinctive of such processes is pivotal to understand pathogenic immune responses and manipulate them for therapeutic purposes. Unfortunately, direct investigation of peripheral tissues, enriched in pathogenic T cells, is often impossible or imposingly invasive in humans. Conversely, blood is easily accessible, but pathogenic signatures are diluted systemically as a result of the strict compartmentalisation of immune responses. In this work, we aimed at defining immune mediators shared between the bloodstream and the synovial micro-environment, and relevant for disease activity in autoimmune arthritis.\n\nMethods. CD4+ T cells from blood and synovium of patients with juvenile idiopathic arthritis (JIA) were immunophenotyped by flow cytometry. The TCR repertoire of a circulating subset showing similarity with the synovium was analysed through next-generation sequencing of TCR β-chain CDR3 to confirm enrichment in synovial clonotypes. Finally, clinical relevance was established by monitoring the size of this subset in the blood of patients with JIA and rheumatoid arthritis (RA).\n\nResults. We identified a small subset of circulating CD4+ T cells replicating the phenotypical signature of lymphocytes infiltrating the inflamed synovium. These circulating pathogenic-like lymphocytes (CPLs) were enriched in synovial clonotypes and they exhibited strong production of pro-inflammatory cytokines. Importantly, CPLs were expanded in patients with JIA, who did not respond to therapy, and also correlated with disease activity in patients with RA.\n\nConclusions. CPLs provide an accessible reservoir of pathogenic cells recirculating into the bloodstream and correlating with disease activity, to be exploited for diagnostic and research purposes.","prettyUrl":"Salvatore-2015-AnnRheuDis","following":false,"created":"10/12/2015","featured":false,"publishedDate":"10/26/2015","urlOrId":"Salvatore-2015-AnnRheuDis","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"64d667d7-d4cc-45bd-b83e-8198c1569183","title":"Next Generation Sequencing Reveals Restriction and Clonotypic Expansion of Regulatory T Cells in Juvenile Idiopathic Arthritis","investigator":"Henderson, Lauren","investigatorInstitution":"Boston Children's Hospital, Division of Immunology","publicationName":"Arthritis and Rheumatology","researchArea":"Autoimmune Disorders","prettyUrls":{"21":"Henderson-2015"},"prettyUrlList":["Henderson-2015"],"summary":"Regulatory T (Treg) cells are unable to inhibit effector T (Teff) cells effectively in juvenile idiopathic arthritis (JIA), but the basis for this dysfunction is incompletely understood.  Animal models of autoimmunity and immunodeficiency demonstrate that a diverse and polyclonal Treg repertoire is essential to maintain Treg cell function.\n\nTreg (CD4+CD25+CD127lo) and Teff (CD4+CD25-) cells were isolated from peripheral blood (PB) and synovial fluid (SF) obtained from JIA patients, controls, and children with Lyme arthritis.  Treg cell function was measured in suppressive assays.  \n\nThe JIA PB Treg repertoire was found to be restricted and clonotypic expansions were found in JIA SF and PB Treg cells.  JIA SF Treg clonality was inversely associated with suppressive capacity.  Skewed TRB variable family and joining gene usage, including overuse of gene segments that have been associated with other autoimmune conditions, was observed.  JIA patients shared a substantial portion of SF Treg clonotypes that were private to JIA and not identified in Lyme arthritis.  \n\nThese findings suggest that abnormalities in the Treg repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.","prettyUrl":"Henderson-2015","following":false,"created":"07/09/2015","featured":false,"publishedDate":"08/10/2015","urlOrId":"Henderson-2015","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"d8ca8feb-0775-4708-bcc5-b2a97cd27836","title":"Deep Sequencing of the T-cell Receptor Repertoire Demonstrates Polyclonal T-cell Infiltrates in Psoriasis","investigator":"Harden, Jamie","investigatorInstitution":"Laboratory for Investigative Dermatology","publicationName":"F1000Research","researchArea":"Dermatology","prettyUrls":{"20":"Harden-2015-F1000Res"},"prettyUrlList":["Harden-2015-F1000Res"],"summary":"It is well known that infiltration of pathogenic T-cells plays an important role in psoriasis pathogenesis. However, the antigen specificity of these activated T-cells is relatively unknown. Previous studies using T-cell receptor polymerase chain reaction technology (TCR-PCR) have suggested there are expanded T-cell receptor (TCR) clones in psoriatic skin, suggesting a response to an unknown psoriatic antigen. Here we describe the results of high-throughput deep sequencing of the entire alpha/beta- and gamma/delta- TCR repertoire in normal healthy skin and psoriatic lesional and non-lesional skin. From this study, we were able to determine that there is a significant increase in the abundance of unique beta- and gamma- TCR sequences in psoriatic lesional skin compared to non-lesional and normal skin, and that the entire T-cell repertoire in psoriasis is polyclonal, with similar diversity to normal and non-lesional skin. Comparison of the alpha/beta- and gamma/delta- TCR repertoire in paired non-lesional and lesional samples showed many common clones within a patient, and these close were often equally abundant in non-lesional and lesional skin, again suggesting a diverse T-cell repertoire. Although there were similar (and low) amounts of shared beta-chain sequences between different patient samples, there was significantly increased sequence sharing of the gamma-chain in psoriatic skin from different individuals compared to those without psoriasis. This suggests that although the T-cell response in psoriasis is highly polyclonal, particular gamma/delta- T-cell subsets may be associated with this disease. Overall, our findings present the feasibility of this technology to determine the entire alpha/beta- and gamma/delta- T-cell repertoire in skin, and that psoriasis contains polyclonal and diverse alpha/beta- and gamma/delta- T-cell populations.","prettyUrl":"Harden-2015-F1000Res","following":false,"created":"07/08/2015","featured":false,"publishedDate":"07/21/2015","urlOrId":"Harden-2015-F1000Res","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c5ead14f-e1fc-4c87-bc0d-763c0f256a82","title":"High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia","investigator":"Wu, D","investigatorInstitution":"Department of Laboratory Medicine, University of Washington","publicationName":"Science Translational Medicine","researchArea":"MRD","prettyUrls":{"23":"wu-2015-stm"},"prettyUrlList":["wu-2015-stm"],"summary":"High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.","prettyUrl":"wu-2015-stm","following":false,"created":"06/22/2015","featured":false,"publishedDate":"06/23/2015","urlOrId":"wu-2015-stm","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"2c486e90-084e-4889-a423-7fe474bc4683","title":"CMV reactivation drives post-transplant T cell reconstitution and results in defects in the underlying TCRβ repertoire","investigator":"Kean, Leslie","investigatorInstitution":"Ben Towne Center for Childhood Cancer Research","publicationName":"Blood","researchArea":"BMT / Stem Cell Transplant","prettyUrls":{"18":"kean-2015-blood"},"prettyUrlList":["kean-2015-blood"],"summary":"Although CMV reactivation has long been implicated in post-transplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T cell subpopulation sorting with high-throughput sequencing of the T cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T cell reconstitution after unrelated-donor HSCT. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme Bhigh/CD28low/CD57high/CD8+ effector-memory T cells and resulted in a linked contraction of all naïve T cells, including CD31+/CD4+ putative thymic emigrants. TCRβ deep sequencing revealed a striking contraction of CD8+ Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T cell repertoire. Registered to www.Clinicaltrials.gov as #NCT01012492.","prettyUrl":"kean-2015-blood","following":false,"created":"06/22/2015","featured":false,"publishedDate":"06/23/2015","urlOrId":"kean-2015-blood","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"313298e3-3f21-4d13-9a97-213c318dabe0","title":"CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire","investigator":"Ribas, A","investigatorInstitution":"Division of Hematology-Oncology, Department of Medicine, University of California at Los Angeles","publicationName":"Clinical Cancer Research","researchArea":"Cancer Immunotherapy","prettyUrls":{"24":"robert-2014-CCR"},"prettyUrlList":["robert-2014-CCR"],"summary":"Purpose: To evaluate the immunomodulatory effects of cytotoxic T–lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).\n\nExperimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab.\n\nResults: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders.\n\nConclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.","prettyUrl":"robert-2014-CCR","following":false,"created":"05/11/2015","featured":false,"publishedDate":"05/11/2015","urlOrId":"robert-2014-CCR","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"230db7c6-11a3-4e39-9eb9-10089dedc75d","title":"Common clonal origin of central and resident memory T cells following skin immunization","investigator":"Kupper, Thomas S.","investigatorInstitution":"Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Womens Hospital","publicationName":"Nature Medicine","researchArea":"Basic Immunology","prettyUrls":{"6":"kupper-2015-naturemed"},"prettyUrlList":["kupper-2015-naturemed"],"summary":"Central memory T (T<sub>CM</sub>) cells in lymph nodes (LNs) and resident memory T (T<sub>RM</sub>) cells in peripheral tissues have distinct roles in protective immunity. Both are generated after primary infections, but their clonal origins have been unclear.\n\nTo address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HTS) of the gene encoding the T cell receptor (TCR) Beta-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells. For every abundant T<sub>RM</sub> cell clone generated in the skin, an abundant T<sub>CM</sub> cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin T<sub>RM</sub> and LN T<sub>CM</sub> cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires.\n\nAlthough they bore the same TCR, T<sub>RM</sub> cells mediated rapid contact hypersensitivity responses, whereas T<sub>CM</sub> cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin T<sub>RM</sub> cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin T<sub>RM</sub> and LN T<sub>CM</sub> cells in similar numbers from the same naive T cells.","prettyUrl":"kupper-2015-naturemed","following":false,"created":"05/10/2015","featured":false,"publishedDate":"05/11/2015","urlOrId":"kupper-2015-naturemed","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"6788530e-ca9f-4066-a4ca-de7bddc812d1","title":"Functional heterogeneity of human memory CD4+ T cell clones primed by pathogens or vaccines","investigator":"Sallusto, Federica","investigatorInstitution":"Institute for Research in Biomedicine, Università della Svizzera Italiana","publicationName":"Science","researchArea":"Basic Immunology","prettyUrls":{"26":"sallusto-2014-science"},"prettyUrlList":["sallusto-2014-science"],"summary":"Distinct types of CD4+ T cells protect the host against different classes of pathogens. However, whether a given pathogen induces a single type of polarized T cell is unclear. By combining antigenic stimulation and T cell receptor deep sequencing we show that human pathogen- and vaccine-specific T helper 1 (Th1), Th2 and Th17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naïve T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather priming.","prettyUrl":"sallusto-2014-science","following":false,"created":"05/03/2015","featured":false,"publishedDate":"05/03/2015","urlOrId":"sallusto-2014-science","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"3821b211-4d8b-48a9-b927-578ff22d9d32","title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","investigator":"Ribas, Antoni","investigatorInstitution":"University of California Los Angeles - Dept of Pathology & Laboratory Medicine","publicationName":"Nature","researchArea":"Cancer Immunotherapy","prettyUrls":{"12":"tumeh-2014-nature"},"prettyUrlList":["tumeh-2014-nature"],"summary":"Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.","prettyUrl":"tumeh-2014-nature","following":false,"created":"04/15/2015","featured":false,"publishedDate":"04/15/2015","urlOrId":"tumeh-2014-nature","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"ba776dbf-9eba-4cc8-86e5-1eda8a0841bc","title":"Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue","investigator":"Robins, Harlan","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Cancer Immunol Immunother.","researchArea":"TIL","prettyUrls":{"28":"sherwood-2013-cii"},"prettyUrlList":["sherwood-2013-cii"],"summary":"Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.","prettyUrl":"sherwood-2013-cii","following":false,"created":"04/14/2015","featured":false,"publishedDate":"04/14/2015","urlOrId":"sherwood-2013-cii","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"67f5d4a1-908d-4613-a39c-282c9899cd24","title":"High-throughput sequencing of T-cell receptors reveals a homogeneous repertoire of tumour-infiltrating lymphocytes in ovarian cancer","investigator":"Robins, Harlan","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Journal of Pathology","researchArea":"TIL","prettyUrls":{"27":"emerson-2013-jpathol"},"prettyUrlList":["emerson-2013-jpathol"],"summary":"The cellular adaptive immune system mounts a response to many solid tumours mediated by tumour-infiltrating T lymphocytes (TILs). Basic measurements of these TILs, including total count, show promise as prognostic markers for a variety of cancers, including ovarian and colorectal. In addition, recent therapeutic advances are thought to exploit this immune response to effectively fight melanoma, with promising studies showing efficacy in additional cancers. However, many of the basic properties of TILs are poorly understood, including specificity, clonality, and spatial heterogeneity of the T-cell response. We utilize deep sequencing of rearranged T-cell receptor beta (TCRB) genes to characterize the basic properties of TILs in ovarian carcinoma. Due to somatic rearrangement during T-cell development, the TCR beta chain sequence serves as a molecular tag for each T-cell clone. Using these sequence tags, we assess similarities and differences between infiltrating T cells in discretely sampled sections of large tumours and compare to T cells from peripheral blood. Within the limits of sensitivity of our assay, the TIL repertoires show strong similarity throughout each tumour and are distinct from the circulating T-cell repertoire. We conclude that the cellular adaptive immune response within ovarian carcinomas is spatially homogeneous and distinct from the T-cell compartment of peripheral blood.","prettyUrl":"emerson-2013-jpathol","following":false,"created":"04/14/2015","featured":false,"publishedDate":"04/14/2015","urlOrId":"emerson-2013-jpathol","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"4b7dded9-9692-428c-9c3d-23239ddd9153","title":"Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection.","investigator":"Robins, Harlan","investigatorInstitution":"Fred Hutchinson Cancer Research Center","publicationName":"Journal of Virology","researchArea":"Vaccine efficacy","prettyUrls":{"29":"dewitt-2015-jvi"},"prettyUrlList":["dewitt-2015-jvi"],"summary":"A detailed characterization of the dynamics and breadth of the immune response to an acute viral infection, as well as the determinants of recruitment to immunological memory, can greatly contribute to our basic understanding of the mechanics of the human immune system and can ultimately guide the design of effective vaccines. In addition to neutralizing antibodies, T cells have been shown to be critical for the effective resolution of acute viral infections. We report the first in-depth analysis of the dynamics of the CD8(+) T cell repertoire at the level of individual T cell clonal lineages upon vaccination of human volunteers with a single dose of YF-17D. This live attenuated yellow fever virus vaccine yields sterile, long-term immunity and has been previously used as a model to understand the immune response to a controlled acute viral infection.<br><br>We identified and enumerated unique CD8(+) T cell clones specifically induced by this vaccine through a combined experimental and statistical approach that included high-throughput sequencing of the CDR3 variable region of the T cell receptor β-chain and an algorithm that detected significantly expanded T cell clones. This allowed us to establish that <br>(i) on average, ∼2,000 CD8(+) T cell clones were induced by YF-17D, <br>(ii) 5 to 6% of the responding clones were recruited to long-term memory 3 months postvaccination, <br>(iii) the most highly expanded effector clones were preferentially recruited to the memory compartment, and <br>(iv) a fraction of the YF-17D-induced clones could be identified from peripheral blood lymphocytes solely by measuring clonal expansion.\n\n<b>IMPORTANCE:</b> The exhaustive investigation of pathogen-induced effector T cells is essential to accurately quantify the dynamics of the human immune response. The yellow fever vaccine (YFV) has been broadly used as a model to understand how a controlled, self-resolving acute viral infection induces an effective and long-term protective immune response. Here, we extend this previous work by reporting the identity of activated effector T cell clones that expand in response to the YFV 2 weeks postvaccination (as defined by their unique T cell receptor gene sequence) and by tracking clones that enter the memory compartment 3 months postvaccination. This is the first study to use high-throughput sequencing of immune cells to characterize the breadth of the antiviral effector cell response and to determine the contribution of unique virus-induced clones to the long-lived memory T cell repertoire. Thus, this study establishes a benchmark against which future vaccines can be compared to predict their efficacy.","prettyUrl":"dewitt-2015-jvi","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"dewitt-2015-jvi","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"a4f4d006-2b47-4a41-9e31-9c6f1483cd76","title":"TCRB Time Course.","investigator":"Sherwood, Anna","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Basic Immunology","prettyUrls":{"13":"healthy-adult-time-course-TCRB"},"prettyUrlList":["healthy-adult-time-course-TCRB"],"summary":"These samples are from a time course study of repertoire turnover in three healthy adult subjects. Each subject was sampled at regular intervals over a year. For the three middle time points, in addition to PBMC, memory and naive T cells were isolated from each draw. Each sample ID contains the subject ID, the sort population, and the date of the blood draw. Samples consist of either unsorted PBMC, naive T cells, or memory T cells. Each sample was processed as an ultra deep.","prettyUrl":"healthy-adult-time-course-TCRB","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"healthy-adult-time-course-TCRB","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b074425f-3d9c-4151-b7c6-79fcca05eef5","title":"Normal Human PBMC, Deep Sequencing, TCRB vs TCRG comparison.","investigator":"Robins, Harlan","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Basic Immunology","prettyUrls":{"35":"TCRB-TCRG-comparison"},"prettyUrlList":["TCRB-TCRG-comparison"],"summary":"This is a small set of samples run with both TCRB and TCRG to give an idea of what to expect from deep sequencing of PBMC.","prettyUrl":"TCRB-TCRG-comparison","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"TCRB-TCRG-comparison","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"c6fc7a45-3e86-4888-b4af-7d8d347b5c3b","title":"TCRB Example Different Tissues from the Same Patient.","investigator":"Desmarais, Cindy","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Basic Immunology","prettyUrls":{"1":"tissue-comparison-TCRB"},"prettyUrlList":["tissue-comparison-TCRB"],"summary":"Human TCRB repertoire surveyed in blood, dermis and epidermis of a healthy subject.","prettyUrl":"tissue-comparison-TCRB","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"tissue-comparison-TCRB","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"63dfc80f-c9c7-4bd5-b2e4-802f1e90c58e","title":"Bone Marrow From Healthy Adults.","investigator":"Bertucci, Caterina","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"BMT","prettyUrls":{"10":"bone-marrow-healthy-adults-control"},"prettyUrlList":["bone-marrow-healthy-adults-control"],"summary":"Bone marrow aspirate samples taken from healthy adults (18-35), from Asian, African American, Hispanic, and Caucasian donors.  TCRB, TCRG, IGH and IGKL data available.  Fresh bone marrow aspirate specimens were provided from a biorepository. Samples are well-categorized with metadata Tags represent HIV, HCV, HBV status as well as ethnicity.","prettyUrl":"bone-marrow-healthy-adults-control","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"bone-marrow-healthy-adults-control","species":null,"loci":null,"tags":null,"tagCategories":[]},{"projectId":"b4ac7a84-1e69-4d60-8254-845720454d7d","title":"Control Data Set of Healthy Mice and Strain Comparison.","investigator":"Hamm, David E.","investigatorInstitution":"Adaptive Biotechnologies","publicationName":"","researchArea":"Controls","prettyUrls":{"3":"2-mouse-strain-comparison"},"prettyUrlList":["2-mouse-strain-comparison"],"summary":"A control data set of healthy mice.  The data set is comprised of 2 mice from two strains, C57-B6 and Balb-C from Charles River Laboratories. Both individuals are litter-mates, males and approximately 18 weeks old. Samples include spleen and thymus tissue from each mouse.","prettyUrl":"2-mouse-strain-comparison","following":false,"created":"04/09/2015","featured":false,"publishedDate":"04/08/2015","urlOrId":"2-mouse-strain-comparison","species":null,"loci":null,"tags":null,"tagCategories":[]}]