B7-H1 mediated expansion of regulatory T-cells in malignant glioma

B7-H1 介导恶性胶质瘤中调节性 T 细胞的扩增

• 批准号: 8004163
• 负责人: Brian Joobeen Jian
• 金额: $ 5.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004163
• 关键词: Cells; Environment; Event; Glioblastoma; Glioma; Human; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Injury; Link; Malignant Glioma; Malignant neoplasm of brain; Mediating; Molecular; Mutation; Operating Rooms; PTEN gene; Patients; Peripheral; Phenotype; Population; Proteins; Regulatory T-Lymphocyte; Reporting; Self Tolerance; Site; Specimen; Structure; Survival Rate; T-Lymphocyte; Up-Regulation; cancer type; cytokine; human PDCD1LG1 protein; immunopathology; neoplastic cell; peripheral blood; prevent; protein expression; public health relevance; relating to nervous system; tumor

DESCRIPTION (provided by applicant): Regulatory T-cells (Tregs) are well characterized as a suppressive T-cell population, which act by inhibiting immune responses and preventing potential immunopathologies. Normally they function to maintain peripheral self-tolerance through immunomodulatory cytokines and proteins in order to influence the function of other immune cells. Specifically in various cancer types, a higher than normal population of regulatory T-cells has been well documented at the tumor site as well as systemically. The presence of Tregs has been implicated as a potential mechanism of persistent local and systemic immune suppression. In patients with malignant gliomas, an augmented population of regulatory t-cells is observed in both the peripheral blood and tumor site, which has been hypothesized to contribute to the immunosuppressive environment of gliomas. Currently, the molecular events underlying Treg function in malignant glioma are poorly understood. Recently, we have reported that upregulation of the immunosuppressive B7-H1 molecule is a direct molecular consequence of PTEN deletion, which is a frequent mutation in human malignant gliomas. The relevance of this observation to Treg function in malignant glioma has yet to be fully explored, and other groups have shown a link between B7-H1 protein expression and Treg expansion. We hypothesize that one mechanism by which B7-H1 confers immunoresistance in malignant gliomas is by causing a preferential shift in the T-cell infiltrate towards a Treg predominance. We propose to use specimens taken directly from the operating room to study the impact of B7-H1 expression on T-reg expansion in glioma specimens. PUBLIC HEALTH RELEVANCE: 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%. 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 the relationship between B7-H1, an immunosuppressive protein expressed by malignant glioma and regulatory T-cells, a phenotype of T-cell that suppresses immunity.

描述（由申请人提供）：调节性T细胞（T细胞）被充分表征为抑制性T细胞群，其通过抑制免疫应答和预防潜在的免疫病理学起作用。正常情况下，它们通过免疫调节细胞因子和蛋白质来维持外周自身耐受，以影响其他免疫细胞的功能。特别是在各种癌症类型中，在肿瘤部位以及全身都有高于正常的调节性T细胞群体的记录。TcB的存在被认为是持续性局部和全身免疫抑制的潜在机制。 在恶性胶质瘤患者中，在外周血和肿瘤部位都观察到调节性t细胞的增加，这被假设有助于胶质瘤的免疫抑制环境。目前，恶性胶质瘤中Treg功能的分子事件知之甚少。最近，我们报道了免疫抑制性B7-H1分子的上调是PTEN缺失的直接分子后果，而PTEN缺失是人类恶性胶质瘤中常见的突变。这一观察结果与恶性胶质瘤中Treg功能的相关性尚未得到充分研究，其他研究组已显示B7-H1蛋白表达与Treg扩增之间存在联系。我们假设B7-H1在恶性胶质瘤中赋予免疫抗性的一种机制是通过引起T细胞浸润向Treg优势的优先转移。我们建议使用直接取自手术室的标本来研究B7-H1表达对胶质瘤标本中T-reg扩增的影响。 公共卫生相关性：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%。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。在这个建议中，我们试图更好地了解B7-H1，恶性胶质瘤和调节性T细胞，抑制免疫的T细胞表型表达的免疫抑制蛋白之间的关系。