Division of Newborn Medicine and Epigenetics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK.
Nat Commun. 2021 Nov 24;12(1):6831. doi: 10.1038/s41467-021-27179-7.
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.
耗竭的 CD8 T 细胞是免疫检查点阻断治疗的关键靶点，其无效的再激活限制了一些癌症患者的持久获益。在这里，我们证明组蛋白去甲基酶 LSD1 作用于祖细胞耗竭的 CD8 T 细胞中，以拮抗 TCF1 介导的祖细胞维持并促进终末分化。因此，遗传干扰或 LSD1 的小分子靶向药物增加了祖细胞耗竭的 CD8 T 细胞的持久性，为增殖转化为数值更大的具有肿瘤杀伤细胞毒性的终末耗竭 T 细胞提供了持续的来源，从而导致对抗 PD1 治疗的有效和持久反应。总的来说，我们的发现为调节 T 细胞耗竭的表观遗传机制提供了重要的见解，并对持久免疫治疗具有重要意义。
