Glioma Associated Macrophages Facilitate Local Immunosuppression

描述（由申请人提供）：肿瘤相关巨噬细胞是癌症先天免疫反应的主要组成部分。虽然巨噬细胞可能通过细胞因子的产生来对抗肿瘤的生长，但它们也可能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）。激活的t细胞在与B7-H1蛋白接触时发生凋亡，使其失效。恶性神经胶质瘤是一种致命的脑肿瘤，以免疫抑制而闻名。几种基于t细胞的免疫治疗方案已经显示出令人印象深刻的外周免疫反应，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。迄今为止，这种现象和B7-H1巨噬细胞介导t细胞凋亡的机制在恶性胶质瘤患者中尚未被描述。在本研究中，我们假设胶质瘤相关巨噬细胞通过表达B7-H1蛋白并诱导t细胞凋亡来抑制局部免疫。为了支持这一假设，我们发现：1)巨噬细胞是浸润恶性胶质瘤的主要免疫细胞，2)B7-H1蛋白的表达受PI3Kinase通路的调控，3)mcp1和mcp3在恶性胶质瘤中高水平表达，4)经胶质瘤条件介质处理的巨噬细胞增加了B7-H1蛋白的表达并诱导t细胞凋亡。

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.