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Cell. 2019 Feb 7;176(4):775-789.e18. doi: 10.1016/j.cell.2018.11.043. Epub 2018 Dec 27.

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

Author information

1
Department of Immunology, Weizmann Institute, Rehovot, Israel.
2
Department of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.
4
Department of Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
5
Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Medical Oncology Department, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
6
Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
7
Department of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: t.schumacher@nki.nl.
8
Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot, Israel. Electronic address: amos.tanay@weizmann.ac.il.
9
Department of Immunology, Weizmann Institute, Rehovot, Israel. Electronic address: ido.amit@weizmann.ac.il.

Abstract

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.

KEYWORDS:

T cell dysfunction; immune checkpoints; immunology; immunotherapy; melanoma; single-cell RNA-seq; tumor immunology; tumor microenvironment; tumor reactivity

PMID:
30595452
DOI:
10.1016/j.cell.2018.11.043

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