封锁
祖细胞
细胞毒性T细胞
CD8型
脱甲基酶
癌症研究
免疫疗法
祖细胞
免疫检查点
免疫系统
癌症免疫疗法
表观遗传学
细胞生物学
生物
免疫学
干细胞
遗传学
受体
基因
体外
作者
Yi Liu,Brian Debo,Mingfeng Li,Zhennan Shi,Wanqiang Sheng,Yang Shi
标识
DOI:10.1038/s41467-021-27179-7
摘要
Abstract Exhausted CD8 + T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8 + T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8 + T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.
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