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Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Li, Hanjie, van der Leun, Anne M., Yofe, Ido, Lubling, Yaniv, Gelbard-Solodkin, Dikla, van Akkooi, Alexander C.J., van den Braber, Marlous, Rozeman, Elisa A., Haanen, John B.A.G., Blank, Christian U., Horlings, Hugo M., David, Eyal, Baran, Yael, Bercovich, Akhiad, Lifshitz, Aviezer, Schumacher, Ton N., Tanay, Amos, Amit, Ido
Cell 2019 v.176 no.4 pp. 775-789.e18
CD8-positive T-lymphocytes, cytotoxicity, genes, humans, immunotherapy, melanoma, patients
Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector “transitional” into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.