胶质母细胞瘤的免疫治疗是目前研究的重点和难点。我们前期工作发现Neddylation抑制剂Pevonedistat能够显著增加胶质母细胞瘤细胞中PD-L1的表达，并与anti-PD-L1免疫检查点阻断抗体协同抑制移植瘤的生长。但Neddylation通路调控PD-L1蛋白的具体机制仍不十分明确。本课题前期工作发现，Cullin5-SOCS3泛素连接酶复合体能够负向调控PD-L1的表达，但并不与PD-L1相互作用，而是通过泛素化降解一个正调控PD-L1的膜蛋白CMTM6来实现的。本课题拟在深入探究Cullin5-SOCS3通过CMTM6间接调控PD-L1蛋白水平的分子机制及其重要性，并利用原位移植瘤动物模型研究Cullin5-SOCS3/CMTM6调控轴在Pevonedistat与anti-PD-L1协同抑制肿瘤细胞中的作用。本课题将为提高胶质母细胞瘤免疫治疗的有效性提供新的思路和理论依据。

There is a dire need for improving current immunotherapy efficacy in glioblastoma. We have recently reported that genetic or pharmacological inhibition of neddylation pathway substantially elevates PD-L1 expression in glioblastoma cells, and the combination of pevonedistat with anti-PD-L1 therapy compared to each agent alone significantly increases the therapeutic efficacy in vivo. Here we have found that Cullin5-SOCS3 ubiquitin ligase complex negatively regulates PD-L1 protein levels in glioblastoma cells. Interestingly, Cullin5-SOCS3 complex does not bind to PD-L1, but interacts with CMTM6 and mediates polyubiquitination and degradation of CMTM6, a type III membrane protein and positive regulator of PD-L1 protein. We will elucidate underlying mechanisms of the regulation of PD-L1 protein by Cullin5-SOCS3/CMTM6 axis and investigate its biological significance. Additionally, we will examine the functions of Cullin5-SOCS3/CMTM6 axis in the synergistic inhibitory effects of Pevonedistat and anti-PD-L1 treatment in mouse glioblastoma orthotopic model. We aim to provide substantial rationale for related clinical trials in future.