氧化应激通过Nr4a2调控小胶质细胞抑制宿主CD8细胞功能介导胶质瘤免疫逃逸的机制研究

胶质母细胞瘤有效的免疫治疗需要激活CD8+T细胞的抗肿瘤作用，但大量小胶质细胞浸润和极化促进肿瘤恶性进展。目前小胶质细胞是否参与和如何介导胶质瘤免疫逃逸的机制尚不清楚。通过前期实验发现氧化应激下小胶质细胞抑制CD8+T细胞浸润及功能并促进GBM进展；通过基因组学和生物信息学分析，发现Nr4a2可能作为氧化应激下小胶质细胞抑制CD8+T细胞的关键转录因子；Chip-seq分析发现Nr4a2可能通过调控Il10和Ezh2的表达抑制CD8+T细胞功能和抗原提呈。在此基础上，本项目拟阐明氧化应激下小胶质细胞抑制CD8+T细胞的分子机制，明确Nr4a2在小胶质细胞抑制CD8+T细胞中的生物学功能，评价干预Nr4a2-Il10/Ezh2信号通路对GBM预后的影响。本项目的实施进一步明确小胶质细胞抑制CD8+T细胞介导胶质瘤免疫逃逸的分子机制和为研发GBM潜在治疗药物以及探寻新型治疗策略提供理论依据。

Efficient immunotherapy in glioblastoma (GBM) require the activation of anti-tumor CD8(+) T cells. However, the infiltration and polarization of microglia in GBM are the critical factors for malignant progress. The mechanism of microglia involving in the inhibition of CD8(+) T cells is still unclear. Our preliminary work showed that microglia under oxidative stress inhibited the infiltration and function of CD8(+) T cells and promoted the progress of GBM both in vivo and in vitro. Genomic data suggested that Nr4a2 in microglia might be the major regulatory factors to inhibit CD8(+) T cells. Chip-seq analysis indicated that Nr4a2, as a transcription factor, might regulate the expression of Il10 and Ezh2 to induce the inhibition of anti-tumor CD8(+) T cells and antigen presentation. In this project, we will clarify the molecular mechanism of microglia under oxidative stress inhibiting CD8(+) T cells. In addition, we will evaluate the biological role of Nr4a2- Il10/Ezh2 in microglia-promoted GBM both in vitro and in vivo. Our study will provide new insight into the role of oxidative stress on microglia immunosuppression, which mediate immune escape of gliomas by inhibiting CD8(+) T cells, and provide theoretical basis for development of potential therapeutic drugs or strategies for glioblastoma.