表达APOA1的溶瘤腺病毒调节肿瘤炎性微环境的作用及其机制研究

溶瘤腺病毒具有直接溶瘤及诱导抗肿瘤免疫作用，在临床研究中取得了一定疗效。而病毒诱导的负性炎症免疫和肿瘤炎性环境限制了溶瘤腺病毒的疗效。本课题组前期构建了表达载脂蛋白A1的溶瘤腺病毒（Ad5-APOA1），发现APOA1促进溶瘤病毒复制与扩散、活化CD8+T细胞、抑制部分免疫负性细胞因子、增强溶瘤腺病毒治疗肝癌的疗效。然而APOA1调控肝癌微环境的作用及机理尚不明。前期工作证实Ad5-APOA1显著下调肿瘤细胞和CD8+T细胞内胆固醇水平，其代谢物27-羟固醇（27-HC）在多种肿瘤中均可增强TNFa的促肿瘤作用。因此我们假设，Ad5-APOA1感染肝癌细胞后，分泌APOA1，下调肿瘤及周围细胞内胆固醇和27-HC水平，抑制肿瘤微环境免疫细胞TNF通路活化，抑制免疫负反应，增强溶瘤腺病毒疗效。研究结果将阐明Ad5-APOA1影响肿瘤炎性微环境的具体机制，为日后临床转化提供平台支撑和实践依据。

Due to its direct oncolytic effect and induced anti-tumor immunity, oncolytic adenovirus therapy has achieved certain curative effects in both basic and clinical research. However, the inflammatory environment of the tumor microenvironment itself and the negative regulation of inflammation-related immunity induced by the oncolytic adenovirus itself greatly limit the efficacy of the oncolytic adenovirus. In the previous study, our group constructed an oncolytic adenovirus Ad5-APOA1 that overexpressed apolipoprotein A1(APOA1), and found that it can significantly improve the efficacy of oncolytic adenovirus in liver cancer, and further studies have found that it can significantly inhibit TNF(Tumor necrosis factor, TNF) pathway also activates immunity in CD8+T cell. The mechanism by which apolipoprotein A1 inhibits the TNF pathway is unknown. In vivo and in vitro experiments have found that Ad5-APOA1 can significantly down-regulate cholesterol levels in tumor cells. Cholesterol metabolite 27-hydroxycholesterol(27-hydroxycholesterol, 27-HC) can promote the TNF pathway to promote tumor progression in a variety of tumors. Therefore, we hypothesized that after Ad5-APOA1 infects liver cancer cells, down-regulating the level of cholesterol in the tumor microenvironment inhibits the production of 27-HC, thereby inhibiting the TNF pathway of CD8+ T cells and ultimately improving the efficacy of oncolytic adenovirus. The research results will clarify the specific mechanism of Ad5-APOA1 affecting the inflammatory pathway, and provide platform support and a practical basis for future clinical translational applications.