Olig2通过趋化因子CXCL10对胶质母细胞瘤免疫微环境调控的机制研究

胶质母细胞瘤（GBM）致死率极高。我们前期工作证明Olig2作为GBM肿瘤干细胞的标志物之一，在GBM发生、发展和分子分型调控中起着关键性作用。Olig2缺失的胶质瘤转录组表达谱数据提示Olig2参与免疫相关肿瘤微环境的调控，而机制未明。最近我们发现Olig2可调控趋化因子CXCL10的表达，基于CXCL10在招募免疫细胞及免疫治疗方面都有重要作用，我们推测Olig2可通过CXCL10调控肿瘤免疫微环境及影响肿瘤免疫治疗。本研究将采用小鼠GBM模型研究 Olig2对肿瘤微环境中免疫细胞的募集作用；通过ChIP-qPCR，shRNA干扰实验验证Olig2对CXCL10的表达调控；利用CXCL10过表达或者CRISPR系统敲除CXCL10 研究Olig2如何通过调节CXCL10对肿瘤免疫微环境进行调控；并探索抑制Olig2是否会引起免疫微环境的改变而加强PD-1抗体治疗的效果。

Glioblastoma (GBM), the most common primary malignant brain tumor, remains uniformly fatal despite aggressive therapies. In our previous study, we demonstrated that Olig2, one of the glioblastoma stem cell markers, had pivotal functions in controlling tumor initiation, progression and molecular phenotype. The transcriptional profiles from Olig2 expressing and Olig2 deficient glioma suggest Olig2 could be involved in the immune related tumor microenvironment, however the mechanism is elusive. Recently, we found Olig2 could regulate the expression of chemokine CXCL10. Based on the critical roles of CXCL10 in immune cells recruitment and tumor immunotherapies, we suppose Olig2 could control the GBM immune microenvironment and affect the immunotherapeutic efficacy through CXCL10. In this investigation, we will employ the mouse glioma model to study the effect of Olig2 in immune cell recruitment; we will determine the Olig2 function in CXCL10 regulation through ChIP-qPCR and shRNA knockdown experiment; we will examine how Olig2 controls immune related tumor microenvironment mediated by CXCL10, via overexpression or knocking out of CXCL10; and further, we will explore whether Olig2 could induce the alteration of immune microenvironment to improve the immunotherapeutic efficacy of the PD-1 blockade.