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Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma
Hanjie Li, Anne M. van der Leun, Ido Yofe, Yaniv Lubling, Dikla Gelbard-Solodkin, Alexander C.J. van Akkooi, Marlous van den Braber, Elisa A. Rozeman, John B.A.G. Haanen, Christian U. Blank, Hugo M. Horlings, Eyal David, Yael Baran, Akhiad Bercovich, Aviezer Lifshitz, Ton N. Schumacher, Amos Tanay, Ido Amit
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.