B7-H1 mediated immunosuppression in immunocompetent animal model of gliomas

B7-H1 介导的免疫功能正常的神经胶质瘤动物模型中的免疫抑制

• 批准号: 8458009
• 负责人: Aaron John Clark
• 金额: $ 5.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-26 至 2014-02-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458009
• 关键词: Adjuvant Therapy; Affect; Animal Model; Animals; Antibodies; Antigens; Ants; Apoptosis; Autologous; Bioluminescence; Brain; Brain Neoplasms; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Cell Proliferation; Cell Surface Proteins; Cell surface; Cells; Cessation of life; Chemiluminescence assay; Effector Cell; Flow Cytometry; Glioblastoma; Glioma; Goals; Growth; Helper-Inducer T-Lymphocyte; Homologous Gene; Human; IL2RA gene; Immune; Immune response; Immunocompetent; Immunodeficient Mouse; Immunoglobulin G; Immunohistochemistry; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Implant; In Vitro; Intracranial Neoplasms; Lead; Lentivirus Vector; Ligands; Luciferases; Malignant Glioma; Malignant Neoplasms; Measures; Mediating; Modality; Modeling; Monitor; Mus; PTEN gene; Pathway interactions; Patients; Peptides; Placebos; Primary Brain Neoplasms; Production; Proteins; Regulatory T-Lymphocyte; Research; Safety; Specificity; Staining method; Stains; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Tumor Immunity; Tumor Suppressor Proteins; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Western Blotting; anergy; base; cohort; cytokine; cytotoxicity; effective therapy; immunogenic; implantation; incomplete Freund' s adjuvant; insight; neoplastic cell; novel therapeutic intervention; programs; public health relevance; receptor; response; small hairpin RNA; therapy design; tumor; tumor growth; tumor microenvironment; vaccine efficacy; vector

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.

描述（由申请人提供）：该提案的长期目标是优化恶性胶质瘤患者的免疫治疗。一些试验已经显示了胶质瘤疫苗的可行性和安全性，但是大多缺乏胶质瘤免疫治疗有效性的证据。癌症免疫抗性和全身性免疫抑制是有效免疫治疗的主要障碍。被设计为引起细胞免疫应答的疫苗疗法依赖于肿瘤特异性CD 8 + T细胞。肿瘤特异性溶细胞性CD 8 + T细胞（CTL）可以对胶质瘤表达的蛋白质产生反应而发生无反应性或凋亡。（B7-H1），也称为程序性死亡配体1（PD-1），是最近发现的细胞表面蛋白，其通过诱导CD 8 + T细胞凋亡、损害细胞因子产生和减少活化T细胞的细胞毒性来抑制抗肿瘤免疫。在神经胶质瘤和其他癌症中，B7-H1表达也与CD 4+免疫抑制性T细胞（TcB）的局部扩增和CD 4+辅助性T细胞（Thelp）的凋亡相关。在本建议中，我们奋进使用免疫活性动物模型更直接地研究B7-H1的作用。GL 261/C57 Blk模型具有测试颅内肿瘤B7-H1表达重要性的所有必要组件，包括：1）可以在整个脑中循环并浸润肿瘤的免疫效应细胞的完整库，2）稳健表达B7-H1的神经胶质瘤，3）可以被遗传操作以降低B7-H1表达的神经胶质瘤，4）可以用针对B7-H1或其受体PD-1的抗体处理以降低B7-H1介导的效应的动物宿主，和5）用已知的胶质瘤相关抗原免疫原性的胶质瘤，所述胶质瘤相关抗原可以用特异性肽如GARC-177-85和EphA 2671 -679进行疫苗接种来靶向。我们将确定GL 261肿瘤细胞表达B7-H1是否诱导局部免疫耐药性，从而影响肿瘤生长、免疫肿瘤微环境和对疫苗治疗的反应。