Glioma Associated Macrophages Facilitate Local Immunosuppression

描述(申请人提供)：肿瘤相关巨噬细胞是癌症先天免疫反应的主要组成部分。虽然巨噬细胞可以通过产生细胞因子来对抗肿瘤生长，但它们也可以自相矛盾地抑制局部免疫。在一些癌症中，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)。激活的T细胞在与B7-H1蛋白接触时会发生凋亡，使其失效。恶性胶质瘤是一种致命的脑肿瘤，以免疫抑制著称。一些基于T细胞的免疫治疗方案显示了令人印象深刻的外周免疫学反应，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，部分是由胶质瘤中发现的B7-H1+巨噬细胞介导的。到目前为止，在恶性胶质瘤患者中，这种现象和B7-H1巨噬细胞介导的T细胞凋亡的机制尚未被描述。在这个方案中，我们假设胶质瘤相关巨噬细胞可以通过B7-H1蛋白的表达和相关的诱导T细胞凋亡来抑制局部免疫。支持这一假设的研究表明：1)巨噬细胞是恶性胶质瘤的主要免疫细胞；2)B7-H1蛋白的表达是通过PI3Kinase途径调节的；3)已知的募集巨噬细胞并激活PI3K的MCP1和MCP3在恶性胶质瘤中高水平表达；4)经胶质瘤条件培养液处理的巨噬细胞B7-H1蛋白表达增加，并诱导T细胞凋亡。 与公共卫生相关：美国每年新诊断的中枢神经系统癌症病例超过17,000例，每年导致超过13,000人死亡。原发的恶性脑肿瘤通常是致命的，最高级别的恶性胶质细胞肿瘤--多形性胶质母细胞瘤--的5年生存率不到2%。传统治疗方式的改进为恶性胶质瘤患者提供了一些生存时间的延长。然而，与术后治疗相关的治疗副作用往往是灾难性的。例如，放射治疗引起的坏死与局灶性脑病理引起的认知障碍有关。长期存活的患者在接受放射治疗后，通常会出现神经元和正常的胶质细胞损伤，而化疗的全身副作用也可能是毁灭性的。归根结底，长期的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，免疫治疗和基因治疗等实验性治疗方法正越来越频繁地应用于恶性胶质瘤患者。免疫疗法特别吸引人，因为它提供了专门针对肿瘤细胞的可能性，而不会损伤正常的神经和神经胶质结构。在这项建议中，我们试图更好地了解有助于局部免疫耐药的肿瘤微环境的各个方面。在这里，我们将重点研究免疫抑制蛋白B7-H1在浸润性肿瘤的巨噬细胞上的表达之间的关系。我们认为，表达B7-H1蛋白的巨噬细胞会导致局部T细胞死亡，并创造一个免疫抑制环境。

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.