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

被引：813

作者：

Li, Hanjie ^{[1
]}

van der Leun, Anne M. ^{[2
]}

Yofe, Ido ^{[1
]}

Lubling, Yaniv ^{[3
,4
]}

Gelbard-Solodkin, Dikla ^{[1
]}

van Akkooi, Alexander C. J. ^{[5
]}

van den Braber, Marlous ^{[2
]}

Rozeman, Elisa A. ^{[6
,7
]}

Haanen, John B. A. G. ^{[6
,7
]}

Blank, Christian U. ^{[6
,7
]}

Horlings, Hugo M. ^{[8
]}

David, Eyal ^{[1
]}

Baran, Yael ^{[3
,4
]}

Bercovich, Akhiad ^{[3
,4
]}

Lifshitz, Aviezer ^{[3
,4
]}

Schumacher, Ton N. ^{[2
]}

Tanay, Amos ^{[3
,4
]}

Amit, Ido ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Immunol, Rehovot, Israel

[2] Netherlands Canc Inst, Oncode Inst, Dept Mol Oncol & Immunol, Amsterdam, Netherlands

[3] Weizmann Inst Sci, Dept Comp Sci & Appl Math, Rehovot, Israel

[4] Weizmann Inst Sci, Dept Biol Regulat, Rehovot, Israel

[5] Netherlands Canc Inst Antoni van Leeuwenhoek, Dept Surg Oncol, Amsterdam, Netherlands

[6] Netherlands Canc Inst, Dept Mol Oncol & Immunol, Amsterdam, Netherlands

[7] Netherlands Canc Inst Antoni van Leeuwenhoek, Med Oncol Dept, Amsterdam, Netherlands

[8] Netherlands Canc Inst Antoni van Leeuwenhoek, Dept Pathol, Amsterdam, Netherlands

来源：

CELL | 2019年 / 176卷 / 04期

基金：

欧洲研究理事会;

关键词：

IMMUNOTHERAPY; EXHAUSTION; LANDSCAPE; INFECTION; EXPANSION;

D O I：

10.1016/j.cell.2018.11.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 TOR 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.

引用

页码：775 / +

页数：33

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