Macrophage polarization in glioma microenvironment

项目摘要 胶质母细胞瘤(GBM)为IV级胶质瘤，是最常见和最具侵袭性的原发脑肿瘤。 人类。GBM对以肿瘤细胞为靶点的标准细胞毒性和分子疗法具有高度耐药性。 最近，免疫疗法被开发出来，为GBM的治疗带来了巨大的希望。然而， 实体肿瘤的免疫治疗仍然是一个巨大的挑战，主要是由于浸润性和 免疫抑制微环境介导的肿瘤相关T细胞失活。这个 针对肿瘤微环境以抑制GBM进展的新疗法的开发，以克服 肿瘤对细胞毒治疗的耐药性以及加强免疫治疗是当务之急。这里, 我们确定了白介素6在肿瘤免疫抑制和基底膜血管异常中的双重作用， 提示IL-6阻断是一种有希望的单一或联合治疗策略 免疫治疗和化疗，通过激活肿瘤微环境中的T细胞，促进 将药物或T细胞输送至肿瘤。我们的初步研究表明，促肿瘤M2-型 巨噬细胞在空间上接近内皮细胞，允许血管分泌诱导。 巨噬细胞极化。此外，我们还揭示了IL-6和巨噬细胞集落刺激因子-1 (CSF-1)诱导巨噬细胞表达精氨酸酶1，导致巨噬细胞M2极化。我们 结果表明，IL-6和CSF-1通过过氧化物酶体增殖物激活诱导巨噬细胞M2极化 受体-γ依赖的缺氧诱导因子-2α转录激活。最后，利用 一种遗传原位基底膜模型和一种新的内皮特异性IL-6基因敲除小鼠 显示内皮细胞中IL-6的缺失改善了携带GBM的小鼠的存活率，有趣的是，增加了 激活肿瘤相关T细胞，抑制异常血管生成。基于这些结果，我们 假设IL-6对替代巨噬细胞激活介导的免疫抑制和 基底膜中异常的肿瘤血管形成。我们将追求以下目标：1)测试实验疗法 将IL-6中和与免疫检查点抑制或化疗相结合治疗GBM 临床前小鼠模型；2)体内测定内皮细胞IL-6在巨噬细胞M2极化中的作用 3)明确IL-6诱导巨噬细胞M2的机制 极化和血管异常，重点是HIF-2α和PPAR-γ的调节。成功 该项目的完成可能会为肿瘤免疫提供新的见解，并导致开发一种新的 IL-6靶向治疗改善癌症免疫治疗和化疗。

Project Summary Glioblastoma (GBM), the grade IV glioma, is the most common and most aggressive primary brain tumor in humans. GBM is highly resistant to standard cytotoxic and molecular therapies that target tumor cells. Immunotherapies have been exploited recently, holding great promise for GBM treatment. However, immunotherapy of solid tumors remains a big challenge, largely due to insufficient infiltration and inactivation of tumor-associated T cells mediated through immunosuppressive microenvironment. The development of new therapies that target tumor microenvironment to inhibit GBM progression, to overcome tumor resistance to cytotoxic therapies, as well as to strengthen immunotherapy is urgently needed. Here, we identify a dual role of interleukin (IL)-6 in tumor immunosuppression and vascular abnormality in GBM, suggesting IL-6 blockade as a promising sole or combined therapeutic strategy for strengthening immunotherapy and chemotherapy, by activating T cells in tumor microenvironment and enhancing the delivery of drugs or T cells to the tumors. Our preliminary studies reveal that tumor-promoting M2-type macrophages are spatially proximate to ECs in human GBM, permissive for angiocrine-induced macrophage polarization. Furthermore, we revealed that IL-6 and macrophage colony stimulating factor-1 (CSF-1) induced robust arginase 1 expression in macrophages, leading to macrophage M2 polarization. We showed that IL-6 and CSF-1 induced macrophage M2 polarization through peroxisome proliferator-activated receptor (PPAR)-γ-dependent transcriptional activation of hypoxia-inducible factor (HIF)-2α. Finally, utilizing a genetic orthotopic GBM model and a newly developed endothelial-specific IL-6 knockout mice, we showed that IL-6 deletion in ECs improved survival in the GBM-bearing mice, and interestingly, increased activation of tumor-associated T cells, and inhibited aberrant angiogenesis. Based on these results, we hypothesize that IL-6 is critical for alternative macrophage activation-mediated immunosuppression and aberrant tumor vascularization in GBM. We will pursue the following Aims: 1) To test experiment therapy that combines IL-6 neutralization with immune checkpoint inhibition or chemotherapy to treat GBM in preclinical mouse models; 2) To determine the in vivo role of endothelial IL-6 in macrophage M2 polarization and vascular abnormality; and 3) To define the mechanisms by which IL-6 induces macrophage M2 polarization and vascular abnormality with a focus on the regulation by HIF-2α and PPAR-γ. Successful completion of this project may provide new insights into tumor immunity and lead to development of a new IL-6-targeted therapy for improving cancer immunotherapy and chemotherapy.