Glioma Associated Macrophages Facilitate Local Immunosuppression

胶质瘤相关巨噬细胞促进局部免疫抑制

基本信息

  • 批准号:
    8000697
  • 负责人:
  • 金额:
    $ 5.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-08-20 至 2011-08-19
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Tumor-associated macrophages are a major component of the innate immune response to cancer. Although macrophages may combat tumor growth through cytokine production, they can paradoxically suppress local immunity as well. In some cancers, tumor associated macrophages can express the cell surface protein B7-H1 (also known as PD-L1). Activated T-cells undergo apoptosis when they come into contact with B7-H1 protein, rendering them ineffective. Malignant glioma is a deadly form of brain tumor that is notoriously immunosuppressive. Several T-cell based immunotherapy protocols have demonstrated impressive peripheral immunological responses, but have been clinically disappointing. We believe the discordance may be due to local immunoresistance, mediated in part by B7-H1+ macrophages found in glioma. To date, this phenomenon and the mechanism of B7-H1 macrophage mediated T-cell apoptosis has not been described in malignant glioma patients. In this proposal, we hypothesize that glioma associated macrophages can suppress local immunity through B7-H1 protein expression and associated induction of T-cell apoptosis. In support of this hypothesis we show that: 1) Macrophages are the predominant immunological cell infiltrating malignant glioma, 2) B7-H1 protein expression is regulated through the PI3Kinase pathway, 3) MCP 1 and MCP 3 which are known to recruit macrophages and activate PI3kinase are expressed at high levels in malignant glioma, and 4) macrophages treated with glioma conditioned media increase B7-H1 protein expression and induce T-cell apoptosis. PUBLIC HEALTH RELEVANCE: Over 17, 000 new cases of central nervous system cancer are diagnosed annually in the United States, accounting for more than 13,000 deaths each year. Primary malignant brain tumors are uniformly fatal, and the 5-year survival rate for the highest grade of malignant glial neoplasm, glioblastoma multiforme (GBM), is less than 2%. Improvements in conventional treatment modalities have provided some extension of survival for patients harboring malignant gliomas. However the therapeutic side effects associated with treatment after surgery are often disastrous. For example, radiation therapy induced necrosis is associated with cognitive impairment caused by focal brain pathology. Neuronal and normal glial cell injury occurs commonly in the brains of long-term survivors after radiation treatment, while the systemic side effects of chemotherapy can be devastating as well. Ultimately, long-term survival precludes a reasonable quality of life. Patients who present with tumor recurrence during or after the administration of conventional therapies are left with few effective treatment options. As a result, experimental therapies such as immunotherapy and gene therapy are being applied to malignant glioma patients with increasing frequency. Immunotherapy is especially appealing because it offers the potential for specifically targeting tumor cells, without injury to normal neural and glial structures. In this proposal we seek to better understand aspects of the tumor micro-environment that contribute to local immunoresistance. Here we will focus on the relationship between expressions of B7- H1, an immunosuppressive protein, on macrophages that infiltrate the tumor. We believe that macrophages expressing B7-H1 protein will cause local T-cell death, and create an immunosuppressive environment.
描述(由申请方提供):肿瘤相关巨噬细胞是对癌症的先天免疫应答的主要成分。虽然巨噬细胞可以通过产生细胞因子来对抗肿瘤生长,但它们也可以矛盾地抑制局部免疫。在某些癌症中,肿瘤相关巨噬细胞可以表达细胞表面蛋白B7-H1(也称为PD-L1)。活化的T细胞在与B7-H1蛋白接触时发生凋亡,使其无效。 恶性神经胶质瘤是一种致命的脑肿瘤,是臭名昭著的免疫抑制。几种基于T细胞的免疫治疗方案已经证明了令人印象深刻的外周免疫应答,但在临床上令人失望。我们认为这种不一致可能是由于局部免疫抵抗,部分由胶质瘤中发现的B7-H1+巨噬细胞介导。迄今为止,在恶性胶质瘤患者中B7-H1巨噬细胞介导的T细胞凋亡的现象及其机制尚未被描述。在这个提议中,我们假设胶质瘤相关巨噬细胞可以通过B7-H1蛋白表达和相关的T细胞凋亡诱导来抑制局部免疫。为了支持这一假设,我们证明:1)巨噬细胞是浸润恶性胶质瘤的主要免疫细胞,2)B7-H1蛋白表达通过PI 3激酶途径调节,3)已知募集巨噬细胞并激活PI 3激酶的MCP 1和MCP 3在恶性胶质瘤中以高水平表达,4)胶质瘤条件培养液处理巨噬细胞后,B7-H1蛋白表达增加,诱导T细胞凋亡。 公共卫生相关性:在美国,每年诊断出超过17,000例新的中枢神经系统癌症病例,每年导致超过13,000例死亡。原发性恶性脑肿瘤是一致致命的,最高级别的恶性胶质瘤多形性胶质母细胞瘤(GBM)的5年生存率低于2%。传统治疗方式的改进为恶性胶质瘤患者的生存提供了一些延长。然而,与手术后治疗相关的治疗副作用通常是灾难性的。例如,放射治疗诱导的坏死与由局灶性脑病理引起的认知障碍相关。神经元和正常胶质细胞损伤通常发生在放射治疗后长期存活者的大脑中,而化疗的全身副作用也可能是毁灭性的。最终,长期生存排除了合理的生活质量。在常规治疗期间或之后出现肿瘤复发的患者几乎没有有效的治疗选择。因此,实验性治疗如免疫治疗和基因治疗正越来越频繁地应用于恶性胶质瘤患者。免疫疗法特别有吸引力,因为它提供了特异性靶向肿瘤细胞的潜力,而不会损伤正常的神经和神经胶质结构。在这项提案中,我们试图更好地了解肿瘤微环境的各个方面,有助于局部免疫抵抗。在这里,我们将集中在B7- H1,一种免疫抑制蛋白,对巨噬细胞浸润肿瘤的表达之间的关系。我们认为,表达B7-H1蛋白的巨噬细胞将导致局部T细胞死亡,并创造一个免疫抑制环境。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A systematic review of intracranial chondrosarcoma and survival.
对颅内软骨肉瘤和生存的系统评价。
  • DOI:
    10.1016/j.jocn.2009.05.003
  • 发表时间:
    2009-12
  • 期刊:
  • 影响因子:
    2
  • 作者:
    Bloch, Orin G.;Jian, Brian J.;Yang, Isaac;Han, Seunggu J.;Aranda, Derick;Ahn, Brian J.;Parsa, Andrew T.
  • 通讯作者:
    Parsa, Andrew T.
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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:
    $ 5.38万
  • 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:
    $ 5.38万
  • 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:
    $ 5.38万
  • 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:
    $ 5.38万
  • 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:
    $ 5.38万
  • 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:
    $ 5.38万
  • 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:
    8280203
  • 财政年份:
    2012
  • 资助金额:
    $ 5.38万
  • 项目类别:

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