MED12缺失通过去甲基化修饰激活干扰素γ通路增强卵巢癌肿瘤免疫的机制研究

卵巢癌是妇科常见的恶性肿瘤，低免疫反应的微环境导致其对免疫治疗不敏感。干扰素γ通路的激活是免疫反应的基础，在卵巢癌中与较好的预后相关，但机制不清。我们前期研究发现卵巢癌细胞敲除MED12后干扰素γ通路被激活，Th1型趋化因子、MHC-I和PD-L1的表达均上调，其趋化淋巴细胞能力和T细胞毒性增强。临床结果显示，MED12低表达者，CD8+T淋巴细胞浸润越多且预后更好。MED12缺失是如何调控干扰素γ通路？我们前期发现MED12敲除后，甲基化基因表达下调；而甲基化抑制剂能激活干扰素γ通路。因此，本项目拟利用肿瘤-淋巴细胞共培养、体内肿瘤免疫模型等方法深入研究MED12缺失后激活干扰素γ通路，促进淋巴细胞浸润和抗原提呈，促进卵巢癌的肿瘤免疫反应；利用Chip-seq、甲基化和转录组测序阐明MED12缺失通过去甲基化修饰激活干扰素γ通路的机制，为增强卵巢癌肿瘤免疫和免疫治疗提供新的思路和策略。

Ovarian cancer is a common malignant tumor in gynecology. The low immune response microenvironment makes it insensitive to immunotherapy. The activation of the interferon-gamma pathway is the basis of the immune response and is associated with a better prognosis in ovarian cancer, but the mechanism is unclear. Our previous study found that the interferon-gamma pathway was activated in MED12 -deleted ovarian cancer cells, and the expression of Th1 chemokines, MHC-I and PD-L1 were all up-regulated, with enhanced chemotactic lymphocyte ability and T cell toxicity. The clinical results showed that those with low MED12 expression had more CD8+ T lymphocyte infiltration and better prognosis. How does the absence of MED12 regulate the interferon-gamma pathway? We previously found that once MED12 was knocked out, the expression of methylated genes was down-regulated; and methylation inhibitors could activate the interferon-gamma pathway. Therefore, this project intends to use methods such as tumor-lymphocyte co-culture and in vivo tumor immune model to study in depth the activation of interferon gamma pathway after MED12 is missing, promote lymphocyte infiltration and antigen presentation, and promote tumor immune response in ovarian cancer; use Chip- Seq, methylation and transcriptome sequencing to clarify the mechanism by which MED12 deletion activates the interferon-gamma pathway through demethylation modification, and provides new ideas and strategies for enhancing tumor immunity and immunotherapy in ovarian cancer.