在慢性感染或肿瘤中CD8+T细胞会出现功能性耗竭，是疾病的持续进展或恶化的主要原因之一。T细胞耗竭过程中参与转录组及表观基因组变化的调控机制尚不完全清楚。我们已发表的文章以及前期试验显示，表观遗传调控分子UHRF1参与T细胞早期发育及CD8+T细胞免疫应答；结合临床病人样本，以及小鼠肿瘤模型验证了UHRF1的表达和CD8+T细胞抗肿瘤能力正相关，而缺失UHRF1的CD8+T细胞失去抗肿瘤能力、细胞因子分泌减少、呈现耗竭性表型；UHRF1可以结合Tox基因转录起始位点抑制其表达。本项目拟利用单细胞测序技术解析UHRF1如何调控肿瘤肿瘤浸润性CD8+T细胞的耗竭形成；深入解析UHRF1表观遗传学调控TOX表达的分子生物学机制；并构建UHRF1过表达的T细胞和CAR-T细胞，在小鼠肿瘤模型中评估其抗肿瘤活性。本项目为过继细胞转移疗法中的T细胞耗竭以及细胞活性维持问题提供一定的指导意义。

T cell exhaustion is characterized by high expression of inhibitory receptors and widespread transcriptional and epigenetic alterations, but the mechanisms responsible for impaired function in exhausted T cells are not fully understood. Our preliminary data suggests UHRF1 participates in thymocyte development and CD8+ T cell immune response. By analyzing liver cancer and colon cancer clinical specimens, UHRF1 expression is indispensable for CD8+T cells to exert anti-tumor function. This result is also supported by mouse tumor models. Loss of UHRF1 expression leads to deficiency of CD8+ T cells anti-tumor activity and cytokine secretion in vivo, as well as increase of exhaustive phenotype. We have found that UHRF1 can directly bind to transcription start site of Tox, and regulate its expression. This study is aimed to illustrate how UHRF1 regulates the development of exhaustive phenotype in tumor infiltrating CD8+ T cells; further mechanistically study how UHRF1 epigenetically regulates the expression of TOX; by overexpressing UHRF1 in CAR-T cells to prevent the T cell exhaustion, and to evaluate its possible anti-tumor therapeutic application in vivo. In broader term, this study will provide insight into how T cell exhaust as well as how to maintain cell activity for adoptive cell transfer therapy.