免疫逃逸是目前肿瘤研究的热点。项目组前期主要围绕免疫逃逸开展工作。课题组发现B7-H4可以介导胶质瘤免疫逃逸；肿瘤微环境中IL-6可以诱导巨噬细胞/小胶质细胞B7-H4的表达；蛋白质互作及文本挖掘分析IL-6和转录因子STAT3密切相关；生物信息学分析B7-H4上游启动子区存在STAT3转录结合位点。本研究拟在上述基础上：1、利用胶质瘤微环境体内外模型研究IL-6介导的STAT3信号通路转录调控巨噬细胞/小胶质细胞B7-H4的分子机制；2、针对验证的信号通路中的关键节点进行体内外功能验证探讨其对B7-H4介导的免疫逃逸的影响。本课题拟在IL-6/STAT3信号通路介导的巨噬细胞/小胶质细胞B7-H4活化角度深入探讨胶质瘤免疫逃逸的新机制。本项目的实施可建立B7-H4的调控模式，丰富胶质瘤免疫逃逸的分子机制，为胶质瘤的靶向治疗提供新思路。

Immune escape is the hot spot in the study of cancer research. Our previous study found that B7-H4 could regulate the immune escape of glioma. IL-6 could induce the expression of B7-H4 in macrophages/microglia. Protein interaction and text mining analysis demonstrated that IL-6 and STAT3 were closely releted. Bioinformatics analysis identified that there were STAT3 binding sites in the promoter of B7-H4. In this study, we will study the mechanism of IL-6 mediated the STAT3 pathway in regulating B7-H4 in macrophages/microglia both in vitro and in vivo. Futher analyze the key notes certified in above pathway in glioma immune escape. In conclusion, our finding will try to reveal the role of IL-6/STAT3 pathway in regulating B7-H4 mediated immune escape in macrophages/microglia and provide more potential approaches for glioma target therapy in future.

2014年自本研究项目立题通过以后，基于前期研究的基础上，继续开展了脑胶质瘤微环境中IL-6 介导的STAT3 转录调控巨噬细胞/小胶质细胞B7-H4 的机制研究，本项目发现CD133+胶质瘤干细胞和小胶质细胞/巨噬细胞间可通过IL-6和IL-10相互激活B7-H4的表达。IL-6激活的STAT3可结合至B7-H4启动子区域从而促进B7-H4表达。深入地，CD133+细胞可通过B7-H4+小胶质细胞介导免疫抑制功能，当抑制B7-H4表达后，微环境T细胞功能增强并使动物模型肿瘤消退。本研究揭示了胶质瘤微环境中CD133+胶质瘤干细胞和小胶质细胞/巨噬细胞相互“对话”并通过B7-H4介导免疫抑制的机制。此外，项目组还对基于IL-6/ STAT3 /B7-H4通路的胶质瘤临床转化策略进行了初探。