低ApoAI削弱CD8+T细胞免疫监控功能促进子宫内膜癌发展的作用和机制

胰岛素抵抗与子宫内膜癌发生密切相关，但具体机制仍需解析。我们发现，调控免疫系统抑制卵巢癌和结肠癌进展的血清载脂蛋白AⅠ（ApoAⅠ）降低是胰岛素抵抗环境下子宫内膜癌患者的特征性表现。伴随ApoAⅠ水平降低，子宫内膜癌灶中免疫活化CD8+T细胞数量减少，而补充ApoAⅠ可促进CD8+T细胞免疫杀伤活性，提示ApoAⅠ降低可能削弱CD8+T细胞对子宫内膜癌的免疫监控功能而促进其发展。本项目将从临床、动物和细胞分子多层面研究ApoAⅠ对子宫内膜癌组织CD8+T细胞免疫活性和募集的调控作用，具体机制聚焦ApoAⅠ降低是否通过蛋白糖基化修饰干扰HIF-1α介导的能量摄取和趋化因子-CCR7通路，降低CD8+T细胞免疫活性和募集。项目将阐明胰岛素抵抗促子宫内膜癌分子机制，回答临床困扰难题并指引胰岛素抵抗子宫内膜癌干预新策略。

Insulin resistance is closely related to endometrial cancer (EC), but the mechanisms involved are not completely understood. Studies have shown that Apolipoprotein AⅠ (ApoAⅠ) inhibits the tumor progression by regulating the immune system, and we found that decreased ApoAⅠ was a characteristic phenotype in EC patients with insulin resistance. We further demonstrated that in patients with decreased serum ApoAⅠ, the infiltration of immune-active CD8+ T cells was reduced, and supplementation of ApoAⅠ promoted immune CD8+ T cell cytotoxic activity. This suggested that decreased ApoAⅠ may weaken the immune surveillance function of CD8+ T cells on endometrial cancer and promote its development.This project will study the regulatory effects of ApoAⅠ on the immune activity and recruitment of CD8+ T cells in endometrial cancer tissues from multiple aspects of clinical, animal, and cellular molecules. The specific mechanism focuses on whether decreased ApoAⅠ can disturb the HIF-1α-mediated energy intake and chemokine-CCR7 pathway through protein glycosylation modification to reduce CD8+ T cell immune activity and recruitment. The project will elucidate the molecular mechanism of insulin resistance to promote endometrial cancer, answer clinical questions and guide new intervention strategies for endometrial cancer with insulin resistance.