胶质瘤微环境中TRIM28/NICD/miR-124/B7-H4信号通路介导小胶质细胞免疫逃逸的机制研究

Tumor microenvironment is a hot spot in the basic research field of glioma, in which microglia plays an important immunosuppressive role. According to our previous findings, microglia with B7-H4 overexpression is recognized as an immunosuppressive phenotype. In addition, TRIM28 up-regulating glioma cells secret exosome, which expresses miR-124 at a low level, and induce high expression of B7-H4 in microglia at the same time. TRIM28 has been confirmed to bind to NICD, a potential negatively regulatory protein of miR-124. Moreover, B7-H4 is projected as a potential target gene of miR-124 by bioinformatics analysis. Accordingly, we propose a scientific hypothesis that "TRIM28/NICD/miR-124/B7-H4 signaling pathway mediates immune escape of microglia”. In this research, we intend to verify the role which miR-124 plays on the post-transcriptional regulation of B7-H4, and then confirm the impacts of TRIM28/NICD compound on the expression of miR-124 and the immune escape induction of microglia. What is more, the diagnostic value of aforementioned molecules, as well as their value in prediction of prognosis will also be addressed in patients with glioma. In conclusion, our project may reveal a novel mechanism behind the immune escape induction mediated by tumor microenvironment and consequently provide new targets for future immunotherapy.

肿瘤微环境是目前胶质瘤基础研究的热点，小胶质细胞在胶质瘤微环境中扮演重要的负性免疫调控角色。课题组前期工作发现B7-H4高表达的小胶质细胞表现为免疫抑制表型；生物信息学预测B7-H4是miR-124的潜在靶基因；TRIM28上调的胶质瘤细胞上清外泌体中miR-124低表达，并诱发小胶质细胞B7-H4高表达；TRIM28与miR-124的潜在负性调控蛋白NICD相结合。据此，我们提出科学假设“TRIM28/NICD/miR-124/B7-H4信号通路介导小胶质细胞免疫逃逸”，拟揭示miR-124对B7-H4的转录后调控作用，证实胶质瘤细胞中TRIM28/NICD不同表达水平对miR-124表达和分泌的影响以及对小胶质细胞免疫活性的诱导作用，并评估上述通路相关分子应用于胶质瘤的诊断及预后的临床价值。预期结果有望揭示肿瘤微环境诱导胶质瘤免疫逃逸的新模式，提供胶质瘤免疫治疗的新靶点。

肿瘤微环境是目前胶质瘤基础研究的热点，小胶质细胞在胶质瘤微环境中扮演重要的负性免疫调控角色。课题组前期工作发现B7-H4高表达的小胶质细胞表现为免疫抑制表型；生物信息学预测B7-H4是miR-124的潜在靶基因；TRIM28上调的胶质瘤细胞上清外泌体中miR-124低表达，并诱发小胶质细胞B7-H4高表达；TRIM28与miR-124的潜在负性调控蛋白NICD相结合。据此，本课题组进一步就“TRIM28/NICD/miR-124/B7-H4信号通路介导小胶质细胞免疫逃逸”进行了相关研究，揭示了miR-124对B7-H4的转录后的调控作用，证实了胶质瘤细胞中TRIM28/NICD不同表达水平对miR-124表达和分泌的影响以及对小胶质细胞免疫活性的诱导作用，并评估上述通路相关分子应用于胶质瘤的诊断及预后的临床价值。项目结果有望揭示肿瘤微环境诱导胶质瘤免疫逃逸的新模式，提供胶质瘤免疫治疗的新靶点。