Nck1影响子宫内膜癌免疫逃逸的分子机制及靶向抑制研究

子宫内膜癌(EC)是起源于子宫内膜上皮的女性生殖系统恶性肿瘤，免疫逃逸是促其恶化的重要原因，相关机制仍有待阐明。课题组前期发现具促癌作用的酪氨酸激酶衔接蛋白非催化区1(Nck1)可上调EC细胞负性免疫调节分子PD-L1表达，后者进一步介导CD8+T细胞凋亡；生信分析显示Nck1表达与PD-L1表达密切相关；既往研究分别显示Nck1与WIP相互作用，WIP可调控Hippo通路关键效应分子YAP，YAP能够直接调控PD-L1表达；因此，我们推测Nck1可能通过WIP-YAP通路调控PD-L1介导EC免疫逃逸。本课题拟从细胞、动物及临床标本三层面阐明Nck1调控PD-L1介导EC免疫逃逸的分子机制；此外，根据Nck1结构特点制备靶向共价抑制剂，探讨阻断Nck1-PD-L1调控轴在EC中的治疗效应及相关免疫学机制。本课题将有望揭示EC免疫逃逸的新机制，为EC免疫治疗提供理论基础和干预策略。

Endometrial cancer (EC) is the female reproductive system malignant tumor originating from the endometrial epithelium. Immune escape is an important cause of its malignancy, but the relevant mechanisms of immune escape remain to be elucidated. Our preliminary studies have found that the tyrosine kinase non-catalytic region 1 (Nck1), which has a cancer-promoting effect, can up-regulate the expression of PD-L1, a negative immunomodulatory molecule in EC cells, finally leading to the apoptosis of CD8+ T cells. The bioinformatic analysis demonstrates that the expression of Nck1 is closely related to that of PD-L1. Previous studies showed that Nck1 interacts with WIP which regulates the key effector molecule YAP of Hippo pathway, and YAP regulates PD-L1 expression directly. Therefore, we speculate that Nck1 may regulate the PD-L1-mediated EC immune escape through the WIP-YAP pathway. In this study, we intend to elucidate the molecular mechanism of the PD-L1-mediated EC immune escape regulated by Nck1 by using the materials of cells, animals, and clinical specimens. In addition, based on the structural features of Nck1, we will prepare a Nck1-targeted covalent inhibitor to investigate the therapeutic effects and the related immunological mechanisms of blocking Nck1-PD-L1 axis in EC. This study is expected to reveal a novel mechanism of EC immune escape, providing a theoretical rationale and intervention strategy for EC immunotherapy.