B7-H1 mediated immunosuppression in immunocompetent animal model of gliomas

描述（由申请人提供）：本提案的长期目标是优化恶性胶质瘤患者的免疫治疗。一些试验已经表明胶质瘤疫苗的可行性和安全性，然而胶质瘤免疫治疗效果的证据大多缺乏。肿瘤免疫抵抗和全身免疫抑制是有效免疫治疗的主要障碍。旨在激发细胞免疫应答的疫苗疗法依赖于肿瘤特异性CD8+ T细胞。肿瘤特异性细胞溶解性CD8+ T细胞（ctl）在胶质瘤蛋白表达的反应中可发生能量或凋亡。（B7-H1），也被称为程序性死亡配体1 (PD-1)，是最近发现的一种细胞表面蛋白，通过诱导CD8+ T细胞凋亡、损害细胞因子的产生和降低活化T细胞的细胞毒性来抑制抗肿瘤免疫。在胶质瘤和其他癌症中，B7-H1的表达也与CD4+免疫抑制T细胞（Tregs）的局部扩增和CD4+辅助性T细胞（help）的凋亡有关。在目前的建议中，我们试图通过免疫功能动物模型更直接地研究B7-H1的作用。GL261/ C57Blk模型具备检测颅内肿瘤B7-H1表达重要性的所有必要成分，包括：1)一个完整的免疫效应细胞库，它可以在整个大脑中循环并浸润肿瘤，2)一个强烈表达B7-H1的胶质瘤，3)一个可以通过基因操纵来降低B7-H1表达的胶质瘤，4)一个可以用针对B7-H1或其受体PD-1的抗体治疗的动物宿主，以减少B7-H1介导的效应，5)具有已知胶质瘤相关抗原的免疫原性胶质瘤，可通过接种特定肽（如GARC-177-85和EphA2671-679）靶向。我们将确定GL261肿瘤细胞表达B7-H1是否诱导局部免疫抵抗，从而影响肿瘤生长、免疫肿瘤微环境和对疫苗治疗的反应。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to optimize immunotherapy for patients with malignant glioma. Several trials have shown the feasibility and safety of glioma vaccines, however evidence of glioma immunotherapy efficacy is mostly lacking. Cancer immunoresistance and systemic immunosuppression represent major impediments to effective immunotherapy. Vaccine therapies designed to provoke a cellular immune response depend upon tumor specific CD8+ T cells. Tumor-specific cytolytic CD8+ T cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas. (B7-H1), also known as programmed death ligand 1 (PD-1), is a recently discovered cell surface protein that inhibits anti-tumor immunity by inducing CD8+ T cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T cells. In glioma and other cancers, B7-H1 expression has also been associated with local expansion of CD4+ immunosuppressive T cells (Tregs) and apoptosis of CD4+ helper T cells (Thelp). In the present proposal, we endeavor to more directly study the effects of B7-H1 using an immunocompetent animal model. The GL261/ C57Blk model has all the necessary components for testing the importance of B7-H1 expression by intracranial tumor including: 1) a full repertoire of immune effector cells that can circulate throughout the brain and infiltrate tumor, 2) a glioma that robustly expresses B7-H1, 3) a glioma that can be genetically manipulated to decrease expression of B7-H1, 4) an animal host that can be treated with antibodies against B7-H1 or its receptor PD-1 to decrease B7-H1 mediated effects, and 5) a glioma that is immunogenic with known glioma associated antigens that can be targeted with vaccination using specific peptides such as GARC-177-85 and EphA2671-679. We will determine if B7-H1 expression by GL261 tumor cells induces local immunoresistance that affects tumor growth, immunologic tumor microenvironment, and response to vaccine therapy.