HAT1/HMGB1/SET通过调控肿瘤细胞免疫检查点PD-L1表达参与免疫调节的机制研究

免疫检查点通路在肿瘤免疫逃逸中发挥重要作用，表观遗传修饰调控PD-L1发挥免疫调节的研究也备受关注。HAT1是经典的组蛋白乙酰基转移酶，前期工作发现HAT1高表达的同时，免疫检查点PD-L1也高表达，既往构建的稳定敲低HMGB1/SET的肺癌细胞系中，PD-L1的表达更显著，pull-down实验发现HAT1与HMGB1, HMGB1与SET有直接相互作用，所以我们提出“HAT1与HMGB1结合，招募SET三者形成‘乙酰化调节复合物的负反馈调节环’调控HAT1的组蛋白乙酰化活性，影响转录因子结合，进而转录调控PD-L1表达参与免疫调节”的科学假说。本研究将以HAT1为核心，从负反馈调节的角度，深入研究HAT1/HMGB1/SET复合物在肺癌细胞系中的乙酰化调控作用，进一步从转录水平探求肿瘤细胞PD-L1的调控机制，为研究表观遗传学改变在肿瘤免疫调控中的作用及抗肿瘤免疫逃逸提供理论依据。

Immune checkpoint pathway plays an important role in tumor immune escape, and studies on epigenetic modification regulating PD-L1 which play an immunoregulatory role have also attracted much attention. HAT1 is a classical histone acetyltransferase. In the previous work, high expression of HAT1 was found to be associated with immune checkpoint PD-L1. The expression of PD-L1 was more significant in the previously constructed lung cancer cell lines stably knocked down HMGB1/SET. The pull-down experiment found that HAT1 and HMGB1, HMGB1 and SET have direct interactions, so we proposed that " HMGB1 binds to HAT1 and recruits SET to form a 'negative feedback regulatory loop of acetylation-regulating complex' to regulate histone acetylation activity of HAT1，which will affect the binding of transcription factors to the promoter of PD-L1 to regulate the expression of PD-L1. From the perspective of negative feedback regulation, HAT1 will be studied in-depth and the acetylation of HAT1/HMGB1/SET complex will be clarificated in lung cancer cell lines, which further improve the acetylation regulation mechanism, while emphasizing the direct relationship between epigenetic and immune regulation, which provides a theoretical basis for studying the role of epigenetic changes in tumor immune regulation.