B7-H1 Expressing Macrophages Mediate Immunosupression in Glioma

项目摘要 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。接种疫苗的免疫反应在很大程度上依赖于肿瘤特异性CD8+ 细胞溶解T细胞，并可通过诱导T细胞凋亡而被抑制。B7-同系物1(B7-H1)是一个表面 胶质瘤细胞上的蛋白与T细胞上的程序性死亡1(PD-1)受体结合并可诱导无能 或者是细胞凋亡。肿瘤相关巨噬细胞被认为通过以下途径促进局部免疫反应 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 两极分化为促炎(M1)或抗炎(M2)表型，由它们的级联 细胞因子。此外，这一证据表明，肿瘤相关巨噬细胞可以表达B7-H1。 细胞表面并可诱导活化的T细胞凋亡，不依赖于胶质瘤细胞。巨噬细胞- 介导的溶细胞T细胞反应的抑制可能是局部和全身的一个主要因素 在胶质瘤患者中可见免疫耐药。我们将提供初步证据：1)B7-H1在 胶质母细胞瘤患者外周血和肿瘤中巨噬细胞增多，2)胶质瘤细胞可以 通过可溶性因子刺激外周血单核细胞表达B7-H1，3)表达B7-H1 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 激活单核细胞表达B7-H1。基于这些数据，我们假设肿瘤来源的可溶性 胶质瘤因子诱导肿瘤相关巨噬细胞产生IL-10，激活B7- H1通过自分泌信号表达。在本提案中，我们将评估时空分布 B7-H1在肿瘤相关巨噬细胞上的表达与肿瘤负荷的关系 其中B7-H1的表达是诱导的。具体地说，我们将研究IL-10自分泌信号和 激活STAT3通路以评估它们在这一过程中的参与程度。我们也会不偏不倚地 蛋白质纯化方法鉴定导致B7-H1上调的胶质瘤衍生因子 单核细胞。

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.