Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence

被引：195

作者：

Belk, Julia A. ^{[1
,2
]}

Yao, Winnie ^{[3
]}

Ly, Nghi ^{[3
]}

Freitas, Katherine A. ^{[4
,5
]}

Chen, Yan-Ting ^{[6
]}

Shi, Quanming ^{[3
]}

Valencia, Alfredo M. ^{[7
,8
]}

Shifrut, Eric ^{[2
]}

Kale, Nupura ^{[9
]}

Yost, Kathryn E. ^{[10
]}

V. Duffy, Connor ^{[11
]}

Daniel, Bence ^{[2
,3
]}

Hwee, Madeline A. ^{[6
]}

Miao, Zhuang ^{[11
]}

Ashworth, Alan ^{[9
,12
]}

Mackall, Crystal L. ^{[13
,14
,15
,16
]}

Marson, Alexander ^{[2
,9
,12
,13
,17
,18
,19
]}

Carnevale, Julia ^{[2
,9
]}

Vardhana, Santosh A. ^{[6
,13
]}

Satpathy, Ansuman T. ^{[2
,3
,4
,13
,16
]}

机构：

[1] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

[2] Gladstone UCSF Inst Genom Immunol, San Francisco, CA 94158 USA

[3] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Immunol Grad Program, Stanford, CA 94035 USA

[5] Stanford Univ, Sch Med, Stanford Canc Inst, Ctr Canc Cell Therapy, Stanford, CA 94035 USA

[6] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[7] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

[8] Stanford Univ, Wu Tsai Neurosci Inst, Stanford Brain Organogenesis, Stanford, CA 94305 USA

[9] Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[10] Stanford Univ, Sch Med, Canc Biol Program, Stanford, CA 94305 USA

[11] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[12] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[13] Parker Inst Canc Immunotherapy, San Francisco, CA 94305 USA

[14] Stanford Univ, Dept Pediat, Sch Med, Div Pediat Hematol Oncol Stem Cell Transplant & R, Stanford, CA 94305 USA

[15] Stanford Univ, Dept Pediat, Sch Med, Div BMT & Cell Therapy, Stanford, CA 94305 USA

[16] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA

[17] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[18] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[19] Univ Calif Berkeley, Innovat Genom Inst, Berkeley, CA 94720 USA

来源：

CANCER CELL | 2022年 / 40卷 / 07期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

EPIGENETIC LANDSCAPE; CANCER; DYSFUNCTION; SUBSETS; INTERROGATION; ACCESSIBILITY; INFECTION; DISCOVERY; COOPERATE; STATES;

D O I：

10.1016/j.ccell.2022.06.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly un-derstood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to system-atically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. In vivo CRISPR screens in murine and human tumor models demonstrated that perturbation of the INO80 and BAF chromatin remodeling complexes improved T cell persistence in tumors. In vivo Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chro-matin accessibility and led to improved antitumor immunity. In summary, we provide an atlas of the genetic regulators of T cell exhaustion and demonstrate that modulation of epigenetic state can improve T cell responses in cancer immunotherapy.

引用

页码：768 / +

页数：27

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