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

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Genome-wide CRISPR screens of T cell exhaustion identify chromatin remodeling factors that limit T cell persistence
Cancer Cell ( IF 48.8 ) Pub Date : 2022-06-23 , DOI: 10.1016/j.ccell.2022.06.001
Julia A Belk ₁ , Winnie Yao ₂ , Nghi Ly ₂ , Katherine A Freitas ₃ , Yan-Ting Chen ₄ , Quanming Shi ₂ , Alfredo M Valencia ₅ , Eric Shifrut ₆ , Nupura Kale ₇ , Kathryn E Yost ₈ , Connor V Duffy ₉ , Bence Daniel ₁₀ , Madeline A Hwee ₄ , Zhuang Miao ₉ , Alan Ashworth ₁₁ , Crystal L Mackall ₁₂ , Alexander Marson ₁₃ , Julia Carnevale ₁₄ , Santosh A Vardhana ₁₅ , Ansuman T Satpathy ₁₆

Affiliation

Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
Department of Pathology, Stanford University, Stanford, CA 94305, USA.
Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94035, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94035, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Parker Institute of Cancer Immunotherapy, San Francisco, CA 94305, USA; Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94035, USA; Division of BMT and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94035, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94305, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94305, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA 94035, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

T cell exhaustion limits antitumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic stimulation assay, we performed genome-wide CRISPR-Cas9 screens to systematically discover regulators of T cell exhaustion, which identified an enrichment of epigenetic factors. 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. Perturb-seq revealed distinct transcriptional roles of each complex and that depletion of canonical BAF complex members, including , resulted in the maintenance of an effector program and downregulation of exhaustion-related genes in tumor-infiltrating T cells. Finally, depletion limited the acquisition of exhaustion-associated chromatin 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.

中文翻译：

T 细胞耗竭的全基因组 CRISPR 筛选可识别限制 T 细胞持久性的染色质重塑因子

T 细胞耗竭限制了抗肿瘤免疫，但这一过程的分子决定因素仍然知之甚少。使用慢性刺激测定，我们进行了全基因组 CRISPR-Cas9 筛选，系统地发现了 T 细胞耗竭的调节因子，从而鉴定出表观遗传因子的富集。小鼠和人类肿瘤模型中的 CRISPR 筛选表明，INO80 和 BAF 染色质重塑复合物的扰动可改善 T 细胞在肿瘤中的持久性。 Perturb-seq 揭示了每个复合体的不同转录作用，以及典型 BAF 复合体成员（包括）的消耗，导致肿瘤浸润 T 细胞中效应程序的维持和耗竭相关基因的下调。最后，耗尽限制了与耗竭相关的染色质可及性的获得，并导致抗肿瘤免疫力的提高。总之，我们提供了 T 细胞耗竭的遗传调节因子图谱，并证明表观遗传状态的调节可以改善癌症免疫治疗中的 T 细胞反应。

更新日期：2022-06-23

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