美国加州大学旧金山分校基因组免疫学研究所Ansuman T. Satpathy团队近期取得重要工作进展，他们通过T细胞耗竭的全基因组CRISPR筛选技术鉴定出了限制T细胞持续存在的染色质重塑因子。相关论文2022年6月23日在线发表于《癌细胞》杂志上。

使用慢性刺激试验，研究人员进行了全基因组CRISPR-Cas9筛选，以系统地发现T细胞耗竭的调节因子，从而确定了表观遗传因子的富集。小鼠和人类肿瘤模型中的体内CRISPR筛选表明，INO80和BAF染色质重塑复合物的扰动改善T细胞在肿瘤中的持久性。体内Perturb-seq揭示了每个复合物的不同转录作用，并且经典BAF复合物成员（包括Arid1a）的消耗导致肿瘤浸润T细胞中效应程序的维持和衰竭相关基因的下调。最后，Arid1a的消耗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，研究人员提供了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细胞应答反应。

据介绍，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。

附：英文原文

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

Author: Julia A. Belk, Winnie Yao, Nghi Ly, Katherine A. Freitas, Yan-Ting Chen, Quanming Shi, Alfredo M. Valencia, Eric Shifrut, Nupura Kale, Kathryn E. Yost, Connor V. Duffy, Bence Daniel, Madeline A. Hwee, Zhuang Miao, Alan Ashworth, Crystal L. Mackall, Alexander Marson, Julia Carnevale, Santosh A. Vardhana, Ansuman T. Satpathy

Issue&Volume: 2022-06-23

Abstract: T cell exhaustion limits antitumor immunity, but the molecular determinants of thisprocess remain poorly understood. Using a chronic stimulation assay, we performedgenome-wide CRISPR-Cas9 screens to systematically 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 ofthe 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 depletionof canonical BAF complex members, including Arid1a, resulted in the maintenance of an effector program and downregulation of exhaustion-relatedgenes in tumor-infiltrating T cells. Finally, Arid1a depletion limited the acquisition of exhaustion-associated chromatin accessibilityand led to improved antitumor immunity. In summary, we provide an atlas of the geneticregulators of T cell exhaustion and demonstrate that modulation of epigenetic statecan improve T cell responses in cancer immunotherapy.

DOI: 10.1016/j.ccell.2022.06.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00231-8