CAR T细胞治疗实体瘤仍未取得实质性突破。耗竭是CAR T细胞失去抗肿瘤功能的内因之一，伴随着表观遗传水平的根本性变化。HDAC抑制剂VPA可通过上调H3K9/K14双乙酰化（diAcH3）水平从根本上恢复小鼠感染模型中耗竭T细胞的效应功能和记忆功能。然而人为改造的CAR T细胞与感染导致的T细胞不同，VPA对CAR T细胞是否具有类似作用还不清楚。我们前期研究发现，VPA也可以通过提高启动子的diAcH3水平从而促进CAR T细胞的细胞因子表达。本项目我们将继续研究VPA对CAR T细胞的增殖、表型、细胞毒性、耗竭以及记忆功能的影响，阐明VPA通过上调diAcH3水平介导的下游通路及分子机制，并在人源化和野生型小鼠肿瘤模型中验证VPA能否改善CAR T细胞治疗实体瘤的效应功能和记忆功能。本项目将为CAR T细胞治疗实体瘤提供基于表观遗传调控的改良策略，具有潜在的临床应用价值。

CAR T cells have yet shown substantial breakthrough in treating solid tumors. One of the limiting factors is exhaustion of CAR T cells leading to the loss of antitumor capacity. Functional exhaustion of T cells is accompanied with fundamental changes at the epigenetic level. HDAC inhibitor VPA could fundamentally reinvigorate exhausted T cells in infectious mouse models through up-regulation of histone H3K9/K14 acetylations (diAcH3), and enhanced the effector and memory responses of antigen-specific T cells.However, CAR T cells are artificially engineered T cells, which are different from T cells generated in infections; it is not clear whether VPA can impose similar effect on CAR T cells. Our preliminary experiments found that VPA could also up-regulate the diAcH3 level at the promoter loci so as to improve the cytokine production capacity of human CAR T cells. In this project, we will continue to define the effects of VPA on the proliferation, phenotype, cytotoxicity, exhaustion and memory function of CAR T cells, and resolve the downstream pathways and molecular mechanism mediated by the VPA-induced up-regulation of diAcH3, and we will also use both humanized and wild-type tumor mouse models to test whether VPA can enhance the anti-tumor effector and memory functions of CAR T cells in vivo. Above all, this project will demonstrate a new strategy based on epigenetic modulations to improve CAR T cell immunotherapies against solid tumors, which has the potential to be used in clinical practice.