人脑胶质瘤募集肿瘤相关巨噬细胞的机制研究

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, while the immunosuppressive microenvironment leads to the emerging immune therapy far from expected. Reversing the immunosuppressive microenvironment of glioma is a promising strategy for immunotherapy. Tumor inflitrating tumor-associated macrophages (TAMs) have a strong immunosuppressive effect, and the maximum proportion among the entire immunosuppressive cells population, rendering them as very important conterparts in tumor immnosuppressive microenvironment. Due to the presence of the blood-brain barrier, the brain is a particular immunologically privileged site. The tumor early infiltrating TAMs 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 TAMs. However, the mechanism of the recruitment of TAMs by glioma cells remains unclear. We regard the collection of TAMs 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 how tumor microenvironment paralyze the movement of TAMs, leading to TAMs accumulation. The aim of this project is to reveal the mechanism of how glioma recruit TAMs to biuld the immunosuppressive microenvironment in a new perspective foucsing on cell movement. The execution of the project would benefit the finding of key targets in reversing tumor immunosuppressive microenvironment, thus providing new immunotherapeutic strategies for human glioma.

人脑胶质瘤是最常见的中枢神经系统恶性肿瘤，手术、放化疗等传统治疗方法效果差，新兴的免疫治疗备受瞩目，但肿瘤抑制性微环境的存在严重制约其疗效。肿瘤相关巨噬细胞（TAMs）是胶质瘤微环境中最多的免疫抑制细胞，具有较强的免疫抑制能力。由于血脑屏障的存在，人脑处于一种特殊的免疫豁免状态，早期TAMs主要来源于脑内固有的小胶质细胞。随着肿瘤进展，外周单核细胞可通过血脑屏障不完整的肿瘤新生血管浸润胶质瘤并被诱导为TAMs。目前胶质瘤细胞募集TAMs的细胞动力学机制仍不清楚。本课题将胶质瘤对TAMs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。从细胞运动的角度分别研究胶质瘤招募脑内固有小脑质细胞及外周单核-巨噬细胞的过程，阐述低氧在胶质瘤募集TAMs过程中的作用，寻找逆转胶质瘤TAMs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的思路。

肿瘤相关巨噬细胞（TAMs）是胶质瘤微环境中最多的免疫抑制细胞，具有较强的免疫抑制能力。由于血脑屏障的存在，人脑处于一种特殊的免疫豁免状态，早期TAMs主要来源于脑内固有的小胶质细胞。随着肿瘤进展，外周单核细胞可通过血脑屏障不完整的肿瘤新生血管浸润胶质瘤并被诱导为TAMs。本课题从细胞运动的角度研究胶质瘤招募脑内固有小脑质细胞及外周单核-巨噬细胞的过程，阐述低氧在胶质瘤募集TAMs过程中的作用，寻找逆转胶质瘤TAMs相关免疫抑制作用的靶点。现有研究表明，胶质瘤相关巨噬细胞以M2型为主，对肿瘤的侵袭性生长具有显著的促进作用。胶质瘤特别是高级别胶质瘤中存在广泛的低氧环境。我们前期研究发现，低氧环境对M2型TAM的聚集具有显著促进作用，暗示低氧在TAM的招募及诱导方面扮演重要角色。本课题研究发现，低氧可以通过TGF-α介导的RTK/PI3K通路促进骨膜蛋白（POSTN）的表达，进而促进TAM的招募。并进一步在体外实验证明了低氧环境及低氧培养下胶质瘤上清会使TAM向M2型极化，且低氧诱导因子（HIF）抑制剂吖啶黄（ACF）的应用可以通过抑制低氧条件下TAM中M-CSFR及低氧胶质瘤中TGF-β的上调，对TAM向M2型极化起到部分抑制的作用，并在体内实验证明了ACF可以抑制肿瘤进展。以上研究结果阐释了低氧对TAM的招募及M2极化的推动作用，并发现通过药物抑制HIF可以减少M2型TAM的积聚并抑制肿瘤进展，为胶质瘤的基因治疗提供了一定的新思路。