Functional B7-H1 expressed by T cells

描述（申请人提供）：B7-H1 （PD-L1）及其受体PD-1是免疫系统中的检查点分子。肿瘤细胞B7-H1表达升高与几种人类癌症疾病的不良预后相关。初步临床观察显示B7-H1阻断剂治疗晚期人类实体肿瘤（肺癌、黑色素瘤和肾癌）有良好的治疗效果。然而，只有一小部分患者有长期的客观反应，尽管在12-41%的治疗患者中观察到疾病的长期稳定。我们令人信服的初步研究表明，T细胞表达的B7-H1先前未知的促生存功能的意外破坏可能是有效阻断治疗的主要障碍。本应用程序的目的是定义B7-H1的T细胞内在功能，评估能够破坏B7-H1内在功能的B7-H1抗体的影响。该建议的中心假设是B7-H1在活化的CD8 T细胞中具有内在的促生存功能，并且是建立保护性免疫所必需的，能够破坏这种功能的B7-H1抗体损害CD8 T细胞介导的抗肿瘤免疫。该建议的临床影响在于，它可能为通过选择最佳抗体来最大化B7-H1阻断治疗提供新的知识和方法。这一建议的基本原理是，T细胞表达的B7-H1的功能作用远未完成。鉴于T细胞是免疫的主要效应器，并且T细胞上B7-H1的表达不是静态的，而是随着激活状态的变化而变化，有必要更详细地研究T细胞相关B7-H1的意义。自从系统性抗体介导的B7-H1阻断被用于多中心I/II期癌症免疫治疗试验以来，这个问题变得更加紧迫。因此，拟议的研究与NIH开发肿瘤免疫治疗新方法的使命有关。在坚实的初步数据支持下，我们的假设将通过追求三个具体目标来验证：(1)确定T细胞内在B7-H1在T细胞分化中的作用；(2)评价B7-H1抗体对T细胞B7-H1内在功能的影响；(3)明确B7-H1在T细胞凋亡中的内在信号通路。我们的研究将提供关于T细胞存活调控的新知识，并为推进B7家族检查点分子和肿瘤免疫治疗领域提供新途径，具有重要意义。

DESCRIPTION (provided by applicant): B7-H1 (PD-L1) and its receptor PD-1 are checkpoint molecules in immune system. Elevated B7-H1 expression on tumor cells has been correlated with poor prognosis in several human cancer diseases. Preliminary clinical observations show promising therapeutic effects of B7-H1 blockade in treating advanced human solid tumors (lung cancer, melanoma and kidney cancers). However, only a small portion of patients have long lasting objective responses, although prolonged stabilization of diseases is observed in 12-41% of treated patients. Our compelling preliminary studies suggest that unanticipated disrupting of a previously unknown pro-survival function of B7-H1 expressed by T cells could be the major impediment to effective blockade therapy. The objective of this application is to define T cell intrinsic function of B7-H1 evaluate the impact of B7-H1 antibody capable of disrupting B7-H1's intrinsic function. The central hypothesis of this proposal is that B7-H1 has an intrinsic pro-survival function in activated CD8 T cells and is required for establishing protective immunity, B7-H1 antibody capable of disrupting this function compromises CD8 T cell-mediated antitumor immunity. The clinical impact of this proposal is that it may provide new knowledge and methods for maximizing B7-H1 blockade therapy by selection of optimal antibody. The rationale of this proposal is that the functional role of B7-H1 expressed by T cells is far from complete. Given that T cells are major effectors of immunity and B7-H1 expression on T cells is not static and varies with activation statuses warrants investigations into the significance of T cell-associated B7-H1 in greater detail. This issue becomes even more urgent since systemic antibody- mediated blockade of B7-H1 is being used in a multiple center phase I/II cancer immunotherapy trials. Thus, the proposed research is relevant to the mission of the NIH to develop new approaches in tumor immunotherapies. Supported by solid preliminary data, our hypothesis will be tested by pursuing three specific aims: (1) To define the role of T cell intrinsic B7-H1 in T cel differentiation; (2) To evaluate the impact of B7-H1 antibody on intrinsic function of B7-H1 in T cells; (3) To define the intrinsic signaling pathway of B7-H1 in T cell apoptosis. The proposed research is significant because our studies will provide new knowledge about regulation of T cell survival and provide new approaches in advancing the fields of B7 family checkpoint molecules and tumor immunotherapy.