A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells

被引：294

作者：

Singer, Meromit ^{[1
]}

Wang, Chao ^{[2
,3
,4
]}

Cong, Le ^{[1
]}

Marjanovic, Nemanja D. ^{[1
,5
,6
]}

Kowalczyk, Monika S. ^{[1
]}

Zhang, Huiyuan ^{[2
,3
,4
]}

Nyman, Jackson ^{[1
]}

Sakuishi, Kaori ^{[2
,3
,4
]}

Kurtulus, Sema ^{[2
,3
,4
]}

Gennert, David ^{[1
]}

Xia, Junrong ^{[2
,3
,4
]}

Kwon, John Y. H. ^{[1
]}

Nevin, James ^{[2
,3
,4
]}

Herbst, Rebecca H. ^{[1
]}

Yanai, Itai ^{[7
,8
]}

Rozenblatt-Rosen, Orit ^{[1
]}

Kuchroo, Vijay K. ^{[2
,3
,4
]}

Regev, Aviv ^{[1
,5
,6
,9
]}

Anderson, Ana C. ^{[2
,3
,4
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA

[3] Harvard Med Sch, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Boston, MA 02115 USA

[5] MIT, Dept Biol, Koch Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] MIT, Ludwig Ctr, Cambridge, MA 02142 USA

[7] NYU, Sch Med, Inst Computat Med, New York, NY 10016 USA

[8] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

[9] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2016年 / 166卷 / 06期

关键词：

INHIBITORY RECEPTORS; EXHAUSTION; EXPRESSION; MELANOMA; TIM-3; PD-1; PATHWAYS; INNATE; LAG-3;

D O I：

10.1016/j.cell.2016.08.052

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：

Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.

引用

页码：1500 / +

页数：21

共 36 条

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