肿瘤相关巨噬细胞通过IL18/JAK/STAT通路促进脑胶质瘤免疫逃逸机制研究

Tumor associated macrophage (TAM) is one of the key members in tumor microenvironment. Accumulating evidences have found that the interaction of glioma cells and tumor microenvironment play important roles in the invasion and malignant progression of gliomas. In previous studies, we have found certain amount of TAM infiltration in gliomas, the extent of which is associated with grade, IDH mutation and prognosis. STAT pathway and PD-L1, prognostic factors in mesenchymal glioma samples, are hyper-activated or over-expressed in this TAM most infiltrated subtype. In this project, we focus on “mechanisms of IL18/JAK/STAT signaling pathways in tumor associated macrophage promoted immune escape of brain gliomas”. We will further validate the association between this signaling pathway and clinicopathological features in patient tissue samples. After that, we will study the biological and potential clinical significance by co-culture, ELISA, flow cytometry, western blot, target inhibition, etc. in glioma cell lines and mouse models. To prove the mechanism, we will study the transcription regulation roles of JAK/STAT pathway on PD-L1 expression. This project has significant translational meanings and will lay a foundation for the clinical application of TAM in the diagnosis, recurrence monitoring and prognosis prediction of gliomas.

肿瘤相关巨噬细胞(TAM)是肿瘤微环境中的重要成员。多项研究发现，脑胶质瘤与肿瘤微环境的相互作用在胶质瘤侵袭与恶性进展中发挥重要作用。课题组前期研究发现，脑胶质瘤中存在TAM浸润，其浸润程度与级别、IDH突变、预后相关；在TAM浸润较多的间质亚型中，存在STAT通路的高激活与PD-L1的高表达，二者均与患者预后相关。本项目集中在“TAM通过IL18/JAK/STAT通路促进脑胶质瘤免疫逃逸机制研究”方向，拟在大样本临床数据中，通过免疫组化等方法，进一步验证上述指标与患者分子病理及临床预后的关系；在细胞及动物模型中，通过共培养、ELISA、流式细胞、蛋白免疫印迹、靶向抑制等方法，明确其生物学意义及潜在临床价值；通过荧光素酶报告实验、ChIP等方法，研究JAK/STAT通路对PD-L1的转录调控作用。本研究为TAM在脑胶质瘤诊断、复发监测、预后判断中开展应用奠定基础，具有重要的转化医学意义。

肿瘤相关巨噬细胞(TAM)是肿瘤微环境中的重要成员。多项研究发现，脑胶质瘤与肿瘤微环境的相互作用在胶质瘤侵袭与恶性进展中发挥重要作用。课题组前期研究发现，脑胶质瘤中存在TAM浸润，其浸润程度与级别、IDH突变、预后相关；在TAM浸润较多的间质亚型中，存在STAT通路的高激活与PD-L1的高表达，二者均与患者预后相关。课题组利用大样本、多中心脑胶质瘤临床样本RNA测序数据、临床肿瘤组织标本、外周血血常规检测结果、患者临床磁共振影像资料等，结合细胞、动物模型，系统分析了肿瘤相关巨噬细胞、外周血免疫状态评估指标、肿瘤样本免疫活性、PIEZO1、糖酵解相关通路、铁死亡相关通路等指标在脑胶质瘤中的生物学及临床意义。进一步验证了前期发现的脑胶质瘤免疫微环境在脑胶质瘤发生、发展中的重要意义。