Tan et al. developed a machine learning classifier (predicTCR) to rapidly predict tumor specificity of TCRs derived from TILs. The authors cloned and experimentally validated 50 TCRs from a metastatic glioblastoma tumor sample, then leveraged these data to train predicTCR for tumor reactivity prediction based on scRNA and VDJ sequencing of TILs (with similar healthy donor data as a negative control). Despite being trained on only one tumor type, predicTCR achieved consistently high rates of accuracy (0.74-0.94) across brain, lung, gastric, and colorectal cancer samples, while the performance of gene signature-based prediction methods was less predictive.
Contributed by Morgan Janes
ABSTRACT: The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR identifies tumor-reactive TCRs in TILs from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity and sensitivity (geometric mean) from 0.38 to 0.74. By predicting tumor-reactive TCRs in a matter of days, TCR clonotypes can be prioritized to accelerate the manufacture of personalized T cell therapies.
Author Info: (1) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Depar
Author Info: (1) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (2) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. Immune Monitoring Unit, National Center for Tumor Diseases, Heidelberg, Germany. (3) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Helmholtz Institute for Translational Oncology, Mainz, Germany. (4) Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany. Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (5) Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Helmholtz Institute for Translational Oncology, Mainz, Germany. Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany. (6) Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. DNA Vector Laboratory, German Cancer Research Center, Heidelberg, Germany. (7) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. (8) Cellply Srl, Bologna, Italy. (9) Cellply Srl, Bologna, Italy. (10) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. (11) BioMed X GmbH, Heidelberg, Germany. (12) DNA Vector Laboratory, German Cancer Research Center, Heidelberg, Germany. (13) Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany. (14) Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center, Heidelberg, Germany. Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (15) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. Immune Monitoring Unit, National Center for Tumor Diseases, Heidelberg, Germany. (16) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. m.platten@dkfz.de. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. m.platten@dkfz.de. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. m.platten@dkfz.de. Immune Monitoring Unit, National Center for Tumor Diseases, Heidelberg, Germany. m.platten@dkfz.de. Helmholtz Institute for Translational Oncology, Mainz, Germany. m.platten@dkfz.de. German Cancer Research Center-Hector Cancer Institute at the Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. m.platten@dkfz.de. (17) CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. e.green@dkfz.de. German Cancer Consortium, Core Center Heidelberg, Heidelberg, Germany. e.green@dkfz.de. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translational Neuroscience, Heidelberg University, Mannheim, Germany. e.green@dkfz.de.
