双特异性磷酸酶DUSP6在肿瘤相关小胶质细胞功能耗竭中的作用及机制

胶质瘤是一种预后极差的颅内原发恶性肿瘤，具有典型免疫逃逸特征。胶质瘤微环境中浸润的小胶质细胞呈MHC-II低表达的功能耗竭状态，难以诱导T细胞发挥抗肿瘤免疫应答。前期研究发现小胶质细胞ERK1/2通路过度活化是引起MHC-II表达抑制的关键原因。而DUSP6作为小胶质细胞特有的ERK1/2抑制因子，其在肿瘤相关小胶质细胞中的表达显著下调。动物模型及临床样本数据表明DUSP6低表达与MHC-II表达抑制相关。此外，DUSP6抑制剂可在体外诱导小胶质细胞功能耗竭状态。因此，我们提出科学假设：肿瘤相关小胶质细胞DUSP6下调，促进ERK1/2通路过度活化，引起MHC-II表达抑制，导致小胶质细胞功能耗竭和胶质瘤免疫逃逸。本研究利用小胶质细胞培养体系和胶质瘤原位模型，通过免疫学、分子生物学、生物信息学手段，研究DUSP6对小胶质细胞功能耗竭的影响，有望为逆转胶质瘤免疫逃逸提供新靶点。

Gliomas, the most common primary malignant tumor in the brain, are notorious for its immune escape characteristics and poor prognosis. Glioma-associated microglia with low expression of MHC-II cannot induce infiltrating T cells to exert anti-tumor immune response. Our previous research found that over-activation of the MAPK/ERK pathway is an important cause of MHC-II expression inhibition in glioma-associated microglia. DUSP6 is a MAPK/ERK signal-specific inhibitor, and its expression in glioma-associated microglia is significantly down-regulated. Therefore, we propose scientific hypotheses: Down-regulation of DUSP6 in microglia promotes MAPK/ERK activation, resulting in inhibition of MHC-II expression and glioma immune escape. In this study, we will study the effect of DUSP6 on the expression of MHC-II in microglia in vitro and in vivo by immunology, molecular biology, and bioinformatics methods. The primary culture system of microglia and the in situ murine glioma model are the main research models. This study is expected to elucidate the molecular mechanism of MHC-II expression in microglia, and provide a new target for intervention of glioma immune escape.