Modulation of Anti-Tumor Immunity by Inhibitory Receptors

项目总结 抑制受体，如PD1和LAG3，协同作用，对T细胞功能施加关键的细胞内在控制， 也有助于调节性T细胞(Tregs)的发育、动态平衡和功能。抑制性 在耗尽的肿瘤浸润性淋巴细胞(TIL)上高表达受体，呈现PD1和LAG3 有效的抗肿瘤免疫的障碍。我们已经证明了组合PD1/LAG3靶向 免疫治疗可使已有肿瘤的小鼠几乎完全缓解。 目的1：PD1和LAG3在预防有效的抗-HBs方面有什么相对和协同作用 CD8+T细胞的肿瘤免疫？我们假设PD1和LAG3协同作用具有显性效应 CD8+TIL，从而介导肿瘤诱导的耐受。我们将使用CD8+限制的Cre介导 PD1/LAG3缺失在肿瘤诱导的CD8+T细胞中的作用 使用可移植和基因诱导的人类癌症模型，特别是黑色素瘤。 目的2：PD1和LAG3在调节肿瘤内Treg功能中的作用是什么？我们 假设“PD1和LAG3限制了Treg的功能，但增强了肿瘤微环境的稳定性”。我们 将使用受限的小鼠确定PD1/LAG3是否有助于肿瘤微环境中的Treg功能 Tregs中的PD1/LAG3缺失。 PPG相互作用：项目2将与项目1合作，确定肿瘤中是否存在抑制性受体丢失- 荷瘤小鼠引发自身免疫损伤，项目3比较肿瘤引起的T细胞耗竭 和慢性病毒感染。在所有AIMS中，项目2将利用核心B获得MICE，核心A获得统计数据 支持，核心C用于转录分析，核心D用于免疫组织学分析。

PROJECT SUMMARY Inhibitory receptors, such as PD1 and LAG3, synergize to exert critical cell intrinsic control of T cell function, but also contribute to the development, homeostasis and function of regulatory T cells (Tregs). Inhibitory receptors are highly expressed on exhausted tumor-infiltrating lymphocytes (TILs), rendering PD1 and LAG3 barriers to effective anti-tumor immunity. We have shown that combinatorial PD1/LAG3 targeted immunotherapy induces almost complete remission in mice with pre-existing tumors. AIM 1: What is the relative and synergistic contributions of PD1 and LAG3 in preventing effective anti- tumor immunity by CD8+ T cells? We hypothesize that “PD1 and LAG3 synergize to have a dominant effect on CD8+ TILs, thereby mediating tumor-induced tolerance”. We will use CD8+-restricted Cre-mediated PD1/LAG3 deletion to assess their relative and mechanistic contribution to tumor-induced CD8+ T cell exhaustion, using transplantable and genetically-induced models of human cancer, especially melanoma. AIM 2: What is the contribution of PD1 and LAG3 in modulating intratumoral Treg function? We hypothesize that “PD1 and LAG3 limit Treg function but enforce stability in the tumor microenvironment”. We will determine if PD1/LAG3 contribute to Treg function in the tumor microenvironment using mice with restricted PD1/LAG3 deletion in Tregs. PPG Interactions: Project 2 will collaborate with Project 1 to determine if inhibitory receptor loss in tumor- bearing mice induces an autoimmune insult, and Project 3 to compare T cell exhaustion induced by tumors and chronic viral infections. In all Aims, Project 2 will utilize Core B to obtain mice, Core A to obtain statistical support, Core C for transcriptional analysis, and Core D for immunohistological analysis.