Macrophage polarization in glioma microenvironment

项目摘要 胶质母细胞瘤（GBM），IV级胶质瘤，是脑内最常见和最具侵袭性的原发性脑肿瘤。 人类GBM对靶向肿瘤细胞的标准细胞毒性和分子疗法具有高度抗性。 最近已经开发了免疫疗法，为GBM治疗带来了巨大的希望。然而，在这方面， 实体瘤的免疫治疗仍然是一个巨大的挑战，主要是由于浸润不足， 通过免疫抑制微环境介导的肿瘤相关T细胞的失活。的 开发靶向肿瘤微环境以抑制GBM进展的新疗法， 肿瘤对细胞毒性疗法的抗性以及加强免疫疗法是迫切需要的。在这里， 我们鉴定了白细胞介素（IL）-6在GBM中的肿瘤免疫抑制和血管异常中的双重作用， 提示IL-6阻断是有希望的单独或联合治疗策略， 免疫疗法和化学疗法，通过激活肿瘤微环境中的T细胞， 将药物或T细胞递送到肿瘤。我们的初步研究表明，促肿瘤M2型 巨噬细胞在空间上接近人GBM中的EC，允许血管分泌诱导的内皮细胞增殖。 巨噬细胞极化此外，我们发现，IL-6和巨噬细胞集落刺激因子-1， （CSF-1）诱导巨噬细胞中的稳健的磷酸化酶1表达，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（PPAR）-γ依赖的低氧诱导因子（HIF）-2α的转录激活。最后利用 一种遗传原位GBM模型和一种新开发的内皮特异性IL-6敲除小鼠，我们 结果表明，内皮细胞中IL-6的缺失改善了携带GBM小鼠的存活率，有趣的是， 激活肿瘤相关T细胞，并抑制异常血管生成。基于这些结果，我们 假设IL-6对于替代性巨噬细胞活化介导免疫抑制是关键的， GBM中的异常肿瘤血管化。本研究的目的是：1）检验实验疗法 联合IL-6中和和免疫检查点抑制或化疗治疗GBM， 2）确定内皮IL-6在巨噬细胞M2极化中的体内作用 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 该项目的完成可能为肿瘤免疫提供新的见解，并导致新的 IL-6靶向治疗用于改善癌症免疫疗法和化学疗法。

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.