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

基本信息

  • 批准号:
    8280203
  • 负责人:
  • 金额:
    $ 13.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(申请人提供):局部免疫抵抗和全身性免疫抑制是胶质瘤有效免疫治疗的主要障碍。免疫应答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-同源1(B7-H1)是胶质瘤细胞表面的一种蛋白,与T细胞上的程序性死亡1(PD-1)受体结合,可诱导无能或凋亡。肿瘤相关巨噬细胞被认为通过抗原递呈和释放特定的细胞因子来促进局部免疫反应。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,这是由其级联的细胞因子定义的。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。巨噬细胞介导的细胞溶解T细胞反应的抑制可能是胶质瘤患者局部和全身免疫耐受的主要因素。我们将提供初步证据:1)胶质母细胞瘤患者外周血和肿瘤中巨噬细胞表面B7-H1的表达增加,2)胶质瘤细胞可以通过可溶性因子刺激外周血单核细胞表达B7-H1,3)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B7-H1的表达。基于这些数据,我们假设来自胶质瘤的肿瘤来源的可溶性因子诱导肿瘤相关巨噬细胞产生IL-10,而IL-10通过自分泌信号激活B7-H1的表达。在这项建议中,我们将评估B7-H1在肿瘤相关巨噬细胞上的时空分布与肿瘤负荷的关系,并探讨B7-H1表达的诱导机制。具体地说,我们将研究IL-10自分泌信号的作用和STAT3途径的激活,以评估它们在这一过程中的参与。我们还将采用一种无偏见的蛋白质纯化方法来鉴定导致单核细胞上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)是一种晚期诊断,尽管目前的治疗标准很低,但存活率很低。人们一直致力于免疫疗法的研究,但局部肿瘤免疫耐药和全身免疫抑制限制了疫苗治疗的临床疗效。肿瘤相关巨噬细胞通过释放抗炎细胞因子在脑胶质瘤中发挥免疫抑制作用。我们现在描述了巨噬细胞免疫耐药的一种新机制,即B7-H1的表面表达,并提出了识别诱导表达的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,以限制胶质瘤诱导的免疫抑制,并提高免疫治疗的效果。

项目成果

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Orin Bloch其他文献

Orin Bloch的其他文献

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{{ truncateString('Orin Bloch', 18)}}的其他基金

Integration of 5-ALA Fluorescence Lifetime Imaging with Stereotactic Surgical Navigation for Quantitative Real-Time Spatial Localization of Tumor During Neurosurgical Procedures
5-ALA 荧光寿命成像与立体定向手术导航相结合,用于神经外科手术过程中肿瘤的定量实时空间定位
  • 批准号:
    10578584
  • 财政年份:
    2023
  • 资助金额:
    $ 13.93万
  • 项目类别:
Label-free fluorescence lifetime imaging for intraoperative real-time guidance of neurological procedures
无标记荧光寿命成像,用于神经系统手术的术中实时指导
  • 批准号:
    10529315
  • 财政年份:
    2020
  • 资助金额:
    $ 13.93万
  • 项目类别:
Label-free fluorescence lifetime imaging for intraoperative real-time guidance of neurological procedures
无标记荧光寿命成像,用于神经系统手术的术中实时指导
  • 批准号:
    10312134
  • 财政年份:
    2020
  • 资助金额:
    $ 13.93万
  • 项目类别:
Fluorescence lifetime technique for intraoperative identification of IDH mutations in brain cancer
荧光寿命技术用于术中识别脑癌 IDH 突变
  • 批准号:
    10044980
  • 财政年份:
    2020
  • 资助金额:
    $ 13.93万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 13.93万
  • 项目类别:
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:
    8463636
  • 财政年份:
    2012
  • 资助金额:
    $ 13.93万
  • 项目类别:
Glioma Associated Macrophages Facilitate Local Immunosuppression
胶质瘤相关巨噬细胞促进局部免疫抑制
  • 批准号:
    8000697
  • 财政年份:
    2010
  • 资助金额:
    $ 13.93万
  • 项目类别:

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