B7-H1 Expressing Macrophages Mediate Immunosupression in Glioma

描述（由申请人提供）： 局部免疫抵抗和全身免疫抑制是胶质瘤有效免疫治疗的主要障碍。对疫苗接种的免疫应答在很大程度上依赖于肿瘤特异性CD 8+细胞溶解性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）是胶质瘤细胞上的表面蛋白，其结合T细胞上的程序性死亡1（PD-1）受体并且可以诱导无反应性或凋亡。肿瘤相关巨噬细胞被认为通过抗原呈递和释放特异性细胞因子来促进局部免疫应答。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，由其细胞因子级联定义。此外，这一证据表明，肿瘤相关巨噬细胞可以在细胞表面表达B7-H1，并可以诱导活化的T细胞凋亡，而不依赖于胶质瘤细胞。巨噬细胞介导的对溶细胞性T细胞反应的抑制可能是胶质瘤患者局部和全身免疫耐药的主要因素。我们将提供以下初步证据：1）胶质母细胞瘤患者外周血和肿瘤中巨噬细胞上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血单核细胞中B7-H1的表达，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，和5）IL-10足以激活单核细胞中的B7-H1表达。基于这些数据，我们假设来自胶质瘤的肿瘤源性可溶性因子诱导肿瘤相关巨噬细胞产生IL-10，其通过自分泌信号激活B7- H1表达。在这个提议中，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。具体而言，我们将研究IL-10自分泌信号和STAT 3通路的激活的作用，以评估它们在这一过程中的参与。我们还将采取无偏倚的蛋白纯化方法来鉴定负责单核细胞上B7-H1上调的胶质瘤衍生因子。 公共卫生相关性： 胶质母细胞瘤（GBM）是一种终末诊断，尽管目前的标准治疗，但生存率很低。许多努力和重点已经放在开发用于治疗GBM的免疫疗法上;然而，局部肿瘤免疫抗性和全身免疫抑制限制了疫苗疗法的临床功效。肿瘤相关巨噬细胞已被证明通过释放抗炎细胞因子在胶质瘤中发挥免疫抑制作用。我们现在描述了一个新的理解机制的免疫耐受的巨噬细胞，表面表达的B7-H1，并提出创新的策略，以确定胶质瘤衍生因子，诱导表达。这项工作有望确定新的干预靶点，以限制胶质瘤诱导的免疫抑制并提高免疫治疗的疗效。

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.