嵌合抗原受体（CAR）T细胞在淋巴瘤的治疗中取得了令人振奋的效果，是肿瘤免疫治疗的革命性进展。然而，对于实体瘤的治疗，CAR-T细胞面临诸多挑战。其中之一是肿瘤微环境作用导致肿瘤特异性T细胞的耗竭。近年来发现，表观遗传特征的改变是T细胞耗竭的重要原因。通过表观遗传学的机制，改变CAR-T细胞表观遗传特征和全局性基因转录，有望增强T细胞的增殖、抗凋亡能力和功能，抵抗耗竭的产生。目前尚缺少这方面的研究。我们的前期研究发现，表观遗传调控因子组蛋白变体H2A.Z对于T细胞的增殖和活化能力发挥重要作用。在此基础上，结合本课题组已建立的EGFRVIII靶向CAR-T模型，我们将在CAR-T细胞中过表达H2A.Z分子，通过体外、体内实验，验证其对CAR-T细胞增殖和功能的促进作用，抵抗耗竭的作用，评价其肿瘤杀伤能力。本项目为克服实体瘤CAR-T治疗中的CAR-T细胞的耗竭问题，提供了新的思路和方法。

Chimeric antigen receptor (CAR) T cell therapy represents a revolutionary treatment for haematological malignancies. However, success has not yet been achieved for solid tumors. CAR-T cell therapy for solid tumors is currently faced with numerous challenges such as physical barriers, the immunosuppressive tumor microenvironment (TME) and the specificity and safety. The interaction of TME with CAR-T cell results in exhaustion of T cells leading to failure of therapy. Epigenetic factors have been shown to play important roles for T cell exhaustion. T cell-intrinsic modification of CAR-T cells with epigenetic factors might provide a novel strategy for CAR-T therapy for solid tumors. Our recent study has found that, histone variant H2A.Z, an epigenetic regulatory factor, is essential for the proliferation and activation of T cells. In this project, we will create H2A.Z modified EGFRVIII CAR-T cells and test whether H2A.Z would enhance CAR-T proliferation and function, and its resistance to exhaustion in vivo.