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。在一些人类癌症疾病中，肿瘤细胞上B7-H1的高表达与预后不良相关。初步临床观察显示，B7-H1阻滞剂在治疗晚期人类实体肿瘤(肺癌、黑色素瘤和肾癌)方面具有良好的疗效。然而，只有一小部分患者有长期的客观反应，尽管在12-41%的接受治疗的患者中观察到了疾病的长期稳定。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中断可能是有效阻断治疗的主要障碍。本应用的目的是确定B7-H1的T细胞固有功能，评价B7-H1抗体对B7-H1‘S固有功能的影响。这一建议的中心假设是，B7-H1在激活的CD8T细胞中具有内在的促生存功能，是建立保护性免疫所必需的，能够破坏这一功能的B7-H1抗体可以损害CD8T细胞介导的抗肿瘤免疫。这一建议的临床影响是，通过选择合适的抗体，可能为最大限度地利用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者，T细胞上B7-H1的表达不是一成不变的，而且随着激活状态的变化而变化，因此有必要更详细地研究T细胞相关的B7-H1的意义。这一问题变得更加紧迫，因为系统性抗体介导的B7-H1阻断正被用于多中心I/II期癌症免疫治疗试验。因此，这项拟议的研究与美国国立卫生研究院开发肿瘤免疫疗法新方法的使命有关。在坚实的初步数据的支持下，我们的假设将通过追求三个特定的目标来验证：(1)确定T细胞内在B7-H1在T细胞分化中的作用；(2)评估B7-H1抗体对T细胞中B7-H1内在功能的影响；(3)确定B7-H1在T细胞凋亡中的内在信号通路。这项拟议的研究具有重要意义，因为我们的研究将提供关于T细胞生存调控的新知识，并在推进B7家族检查点分子和肿瘤免疫治疗领域提供新的方法。

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.