Capitalizing on the high-dimensional capability of CyTOF analysis, Fehlings et al. probed the antigen specificity and phenotypic profile of T cells in mice just prior to tumor rejection, revealing distinctions between tumor and peripheral neoantigen-specific T cells; multiple, phenotypically divergent CD8+ T cell populations within tumors; and convergence in phenotype and reduction in markers of dysfunctionality following anti-CTLA-4 therapy.
The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.
Author Info: (1) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (2) Agency for Science, Technolog
Author Info: (1) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (2) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (3) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (4) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (5) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (6) Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. (7) Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. (8) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. (9) Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, 63110, USA. (10) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), 8 A Biomedical Grove, Singapore, 138648, Singapore. evan_newell@immunol.a-star.edu.sg.
