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: 8280203
• 负责人: Orin Bloch
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280203
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Glioblastoma (GBM) is a terminal diagnosis with poor survival despite current standard of care therapies. Much effort and emphasis has been placed on developing immunotherapy for the treatment of GBM; however, local tumor immunoresistance and systemic immunosuppression have limited the clinical efficacy of vaccine therapies. Tumor-associated macrophages have been shown to exert an immunosuppressive effect in glioma through the release of anti-inflammatory cytokines. We now describe a newly understood mechanism of immunoresistance in macrophages, surface expression of B7-H1, and propose innovative strategies to identify the glioma-derived factor that induces expression. This work promises to identify new targets for intervention to limit glioma-induced immunosuppression and increase the efficacy of immunotherapy.

描述（由申请人提供）：局部免疫抵抗和全身免疫抑制是神经胶质瘤有效免疫治疗的主要障碍。对疫苗接种的免疫反应很大程度上依赖于肿瘤特异性 CD8+ 溶细胞 T 细胞，并且可以通过诱导 T 细胞凋亡来抑制。 B7-同源物 1 (B7-H1) 是神经胶质瘤细胞上的一种表面蛋白，可与 T 细胞上的程序性死亡 1 (PD-1) 受体结合，并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抗原呈递和特定细胞因子的释放来促进局部免疫反应。最近的证据表明，巨噬细胞可以极化为促炎（M1）或抗炎（M2）表型，这由它们的细胞因子级联定义。此外，该证据表明肿瘤相关巨噬细胞可以在细胞表面表达 B7-H1，并且可以诱导活化 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神经胶质瘤患者局部和全身免疫抵抗的主要因素。我们将提供初步证据：1) 胶质母细胞瘤患者的外周血和肿瘤中巨噬细胞上的 B7-H1 表达增加，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) 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，我们假设来自神经胶质瘤的肿瘤衍生可溶性因子诱导肿瘤相关巨噬细胞产生 IL-10，从而通过自分泌信号激活 B7-H1 表达。在本提案中，我们将评估 B7-H1 在肿瘤相关巨噬细胞上相对于肿瘤负荷的时空分布，并研究诱导 B7-H1 表达的机制。具体来说，我们将研究 IL-10 自分泌信号传导和 STAT3 通路激活的作用，以评估它们在此过程中的参与。我们还将采用公正的蛋白质纯化方法来鉴定负责单核细胞上 B7-H1 上调的神经胶质瘤衍生因子。 公共卫生相关性：胶质母细胞瘤 (GBM) 是一种晚期诊断，尽管采用目前的护理治疗标准，但生存率仍很差。人们在开发治疗 GBM 的免疫疗法方面投入了大量的精力和重点；然而，局部肿瘤免疫抵抗和全身免疫抑制限制了疫苗疗法的临床疗效。肿瘤相关巨噬细胞已被证明通过释放抗炎细胞因子在神经胶质瘤中发挥免疫抑制作用。我们现在描述了巨噬细胞中新近了解的免疫抵抗机制，即 B7-H1 的表面表达，并提出了识别诱导表达的神经胶质瘤衍生因子的创新策略。这项工作有望确定新的干预靶点，以限制神经胶质瘤引起的免疫抑制并提高免疫治疗的疗效。