Macrophage polarization in glioma microenvironment

神经胶质瘤微环境中的巨噬细胞极化

基本信息

批准号：
9769177
负责人：
Yi Fan
金额：
$ 40.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769177
关键词：
Animals Antibodies Biological Assay Blood Vessels CTLA4 gene Cell Proliferation Cell physiology Cells Chemotherapy-Oncologic Procedure Combined Modality Therapy Cytotoxic Chemotherapy Data Development Drug Delivery Systems Endothelial Cells Endothelium Excision Genetic Glioblastoma Glioma Goals Growth Growth Factor Human Hypoxia Inducible Factor Immunity Immunologic Monitoring Immunosuppression Immunosuppressive Agents Immunotherapy Infiltration Inflammation Interleukin-10 Interleukin-13 Interleukin-4 Interleukin-6 Investigational Therapies Knockout Mice Lead Macrophage Activation Macrophage Colony-Stimulating Factor Malignant Neoplasms Mediating Modeling Mus Operative Surgical Procedures PPAR gamma Pericytes Permeability Phagocytosis Play Population Primary Brain Neoplasms Radiation Receptor Protein-Tyrosine Kinases Regulation Resistance Role Signal Pathway Solid Neoplasm Source Structure Survival Analysis T-Cell Activation T-Lymphocyte Testing Therapeutic Three-Dimensional Imaging Transcriptional Activation Transforming Growth Factor beta Tumor Angiogenesis Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Vascularization angiogenesis anti-PD-1 arginase base bevacizumab cancer immunotherapy cell motility checkpoint inhibition chemotherapy cytokine cytotoxic experimental study improved in vivo in vivo evaluation insight macrophage molecular targeted therapies mouse model neoplastic cell neutralizing antibody new therapeutic target pre-clinical promoter recruit targeted treatment temozolomide therapy resistant tumor tumor growth tumor microenvironment tumor progression vascular abnormality

项目摘要

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.

项目概要胶质母细胞瘤 (GBM) 是 IV 级胶质瘤，是最常见、最具侵袭性的原发性脑肿瘤。人类 GBM 对针对肿瘤细胞的标准细胞毒性和分子疗法具有高度抵抗力。最近，免疫疗法被开发出来，为 GBM 的治疗带来了巨大的希望。实体瘤的免疫治疗仍然是一个巨大的挑战，很大程度上是由于浸润不足和通过免疫抑制微环境介导的肿瘤相关 T 细胞失活。开发针对肿瘤微环境的新疗法，抑制 GBM 进展，克服肿瘤对细胞毒性疗法的耐药性以及加强免疫疗法是迫切需要的。我们确定了白细胞介素 (IL)-6 在肿瘤免疫抑制和 GBM 血管异常中的双重作用，建议 IL-6 阻断作为一种有前途的单一或联合治疗策略来增强免疫治疗和化疗，通过激活肿瘤微环境中的 T 细胞并增强我们的初步研究表明，M2 型肿瘤促进药物或 T 细胞的递送。巨噬细胞在空间上接近人类 GBM 中的 EC，允许血管分泌素诱导的此外，我们还发现了 IL-6 和巨噬细胞集落刺激因子 1。 (CSF-1) 诱导巨噬细胞中精氨酸酶 1 的强烈表达，导致巨噬细胞 M2 极化。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 极化最后，利用缺氧诱导因子（HIF）-2α 受体（PPAR）-γ 依赖性转录激活。遗传原位 GBM 模型和新开发的内皮特异性 IL-6 敲除小鼠结果表明，EC 中 IL-6 的缺失提高了携带 GBM 的小鼠的存活率，并且有趣的是，增加了激活肿瘤相关 T 细胞，并抑制异常血管生成基于这些结果，我们 IL-6 对于替代巨噬细胞激活介导的免疫抑制至关重要 GBM 中异常的肿瘤血管化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来治疗 GBM 临床前小鼠模型；2) 确定体内内皮IL-6在巨噬细胞M2极化中的作用和血管异常；以及 3) 确定 IL-6 诱导巨噬细胞 M2 的机制极化和血管异常，重点关注 HIF-2α 和 PPAR-γ 的调节。该项目的完成可能会为肿瘤免疫提供新的见解，并导致开发新的 IL-6 靶向治疗可改善癌症免疫治疗和化疗。