B7-H1 Expressing Macrophages Mediate Immunosupression in Glioma

表达 B7-H1 的巨噬细胞介导神经胶质瘤的免疫抑制

• 批准号: 8831805
• 负责人: Orin Bloch
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8831805
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Apoptosis; Autocrine Communication; Binding; Biopsy; Blocking Antibodies; Blood specimen; Brain; CD8B1 gene; Cell surface; Cells; Cessation of life; Conditioned Culture Media; Cytotoxic T-Lymphocytes; Data; Diagnosis; Distal; Enzyme-Linked Immunosorbent Assay; Excision; Flow Cytometry; Glioblastoma; Glioma; Goals; Homologous Gene; Image; Immune response; Immunoblotting; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Interleukin-10; Intervention; Ligands; MRI Scans; Magnetic Resonance Imaging; Malignant Glioma; Mass Spectrum Analysis; Measures; Mediating; Membrane Proteins; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral; Phenotype; Process; Production; Proteins; Relative (related person); Role; STAT3 gene; Serum; Site; Small Interfering RNA; Staining method; Stains; Surface; System; T cell response; T-Lymphocyte; Testing; Time; Tissues; Tumor Burden; Tumor-Derived; Tumor-Secreted Protein; Up-Regulation; Vaccination; Vaccine Therapy; Work; anergy; base; clinical efficacy; cytokine; fast protein liquid chromatography; inhibitor/antagonist; innovation; macrophage; monocyte; novel; overexpression; peripheral blood; programs; progression marker; protein purification; receptor; spatiotemporal; standard of care; tumor

Project Summary Local immunoresistance and systemic immunosuppression represent major impediments to effective immunotherapy for gliomas. The immune response to vaccination is largely dependent on tumor specific CD8+ cytolytic T cells, and can be suppressed by induction of T cell apoptosis. B7-Homologue 1 (B7-H1) is a surface protein on glioma cells that binds to the programmed death 1 (PD-1) receptor on T cells and can induce anergy or apoptosis. Tumor-associated macrophages are thought to contribute to the local immune response through antigen presentation and the release of specific cytokines. Recent evidence suggests that macrophages can be polarized to pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, defined by their cascade of cytokines. In addition, this evidence demonstrates that tumor-associated macrophages can express B7-H1 at the cell surface and can induce apoptosis of activated T cells, independent of glioma cells. Macrophage- mediated suppression of the cytolytic T cell response may be a primary factor in the local and systemic immunoresistance seen in glioma patients. We will provide preliminary evidence that 1) B7-H1 expression on macrophages is increased in peripheral blood and tumor from glioblastoma patients, 2) glioma cells can stimulate B7-H1 expression in peripheral monocytes through a soluble factor, 3) B7-H1 expressing monocytes induce CTL apoptosis, 4) glioma cells stimulate monocytes to produce IL-10, and 5) IL-10 is sufficient to activate B7-H1 expression in monocytes. Based on these data, we hypothesize that tumor-derived soluble factors from gliomas induce IL-10 production in tumor-associated macrophages, which activates B7- H1 expression through autocrine signaling. In this proposal we will evaluate the spatiotemporal distribution of B7-H1 on tumor-associated macrophages relative to tumor burden and investigate the mechanisms by which B7-H1 expression is induced. Specifically, we will study the role of IL-10 autocrine signaling and activation of the STAT3 pathway to evaluate their involvement in this process. We will also take an unbiased protein purification approach to identify the glioma-derived factor responsible for upregulation of B7-H1 on monocytes.

项目概要 局部免疫抵抗和全身免疫抑制是有效治疗的主要障碍。 神经胶质瘤的免疫治疗。对疫苗接种的免疫反应很大程度上取决于肿瘤特异性 CD8+ 溶细胞性 T 细胞，并且可以通过诱导 T 细胞凋亡来抑制。 B7-同系物 1 (B7-H1) 是一个表面 神经胶质瘤细胞上的蛋白质，与 T 细胞上的程序性死亡 1 (PD-1) 受体结合，可诱导无反应性 或细胞凋亡。肿瘤相关巨噬细胞被认为通过以下方式促进局部免疫反应： 抗原呈递和特定细胞因子的释放。最近的证据表明巨噬细胞可以 被极化为促炎（M1）或抗炎（M2）表型，由它们的级联定义 细胞因子。此外，该证据表明肿瘤相关巨噬细胞可以在 细胞表面并可诱导活化 T 细胞凋亡，独立于神经胶质瘤细胞。巨噬细胞- 介导的溶细胞 T 细胞反应抑制可能是局部和全身性损伤的主要因素。 神经胶质瘤患者中出现免疫抵抗。我们将提供初步证据证明 1) B7-H1 表达 胶质母细胞瘤患者的外周血和肿瘤中巨噬细胞增加，2）胶质瘤细胞可以 通过可溶性因子刺激外周单核细胞中的 B7-H1 表达，3) 表达 B7-H1 的单核细胞 诱导 CTL 凋亡，4) 神经胶质瘤细胞刺激单核细胞产生 IL-10，5) IL-10 足以 激活单核细胞中的 B7-H1 表达。基于这些数据，我们假设肿瘤来源的可溶性 神经胶质瘤因子诱导肿瘤相关巨噬细胞产生 IL-10，从而激活 B7- H1 通过自分泌信号表达。在这个提案中，我们将评估时空分布 B7-H1 对肿瘤相关巨噬细胞的影响与肿瘤负荷相关，并通过以下方法研究其机制： 其中 B7-H1 表达被诱导。具体来说，我们将研究 IL-10 自分泌信号传导的作用和 STAT3 通路的激活来评估它们在此过程中的参与情况。我们也将秉持公正的态度 蛋白质纯化方法来鉴定负责上调 B7-H1 的神经胶质瘤衍生因子 单核细胞。