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.

项目总结