中文摘要
人脑作为“免疫特免器官”其区域免疫特性研究较少,仅涉及小胶质细胞的某些天然免疫功能。脑胶质瘤是最常见的中枢神经系统恶性肿瘤,传统疗法效果差。通过深入解析人脑小胶质细胞/巨噬细胞的M1/M2互转极化机制,有助于了解脑胶质瘤发生和逃逸关键因素。胶质瘤相关小胶质细胞/巨噬细胞(GAMs)是胶质瘤微环境中最多的免疫抑制细胞,肿瘤低氧状态可诱导其M2极化。早期GAMs主要来自脑内固有小胶质细胞,随着肿瘤进展,外周单核细胞可浸润至胶质瘤区域并被诱导为GAMs,目前胶质瘤细胞募集GAMs的细胞动力学机制仍不清楚。本课题将胶质瘤对GAMs的募集分为早期固有招募、中期外周招募和晚期恶性积聚三个阶段,从细胞运动角度分别研究胶质瘤招募GAMs的过程,阐述低氧在胶质瘤募集GAMs及M2极化过程中的作用,寻找逆转M2型GAMs相关免疫抑制作用的靶点。本课题将丰富胶质瘤免疫逃逸理论,为人脑胶质瘤的免疫治疗提供新思路。
英文摘要
As an immune privileged site, the brain’s regional immune system has been less studied except for some immune functions of microglias. Human glioma is the most common malignant tumor of the central nervous system, and the efficacy of the traditional therapy such as operation and chemoradiotherapy is poor. By further study into the transformation of M1 and M2 subtype of microglia/macrophage, we can have a better understanding of the tumorigenesis and immune escape of glioma. Tumor infiltrating tumor-associated microglia/macrophages (GAMs) account for the maximum proportion among the entire immunosuppressive cells population and the hypoxia environment in glioma can promote the polarization of the GAMs to M2 subtype. The tumor early infiltrating GAMs are mainly induced from the innate microglia of the brain. As the tumor progression, plenty of peripheral mononuclear cells pass through the incomplete blood brain barrier during tumor neovascularization then induced into glioma infiltrating GAMs. However, the mechanism of the recruitment of M2 GAMs by glioma cells remains unclear. We regard the collection of M2 GAMs by glioma as three coherent stages: early-stage inherent recruit, medium-term peripheral recruit, and late-stage malignant accumulation. Then, we would explore the recruitment mechanism of the innate microglia and peripheral mononuclear cells' motility, and indicate what role does tumor hypoxia microenvironment play in recruitment and M2 polarization of GAMs. More importantly, we would try to find the molecular target of M2 subtype GAMs in its immunosuppressive function. This project will enrich the immune escape theory of glioma and provide new ideas for immunotherapy of glioma.
