A deubiquitination module controls Treg adaptation to tumor microenvironment

项目总结： 癌症治疗的最新进展之一是免疫疗法的发展 通过瞄准检查点受体。然而，免疫疗法的尝试增加了 抗肿瘤免疫反应取得的成功非常有限。肿瘤的主要障碍 免疫治疗是由抑制抗肿瘤功能的调节性T(Treg)细胞介导的 效应器T细胞。谱系转录因子Forkhead Box P3(FoxP3)被称为 Treg在恶劣的肿瘤微环境中的适应程序，如代谢变化 和缺氧。然而，控制FoxP3介导的Treg适应度以协调 肿瘤内Treg细胞的存活和功能尚未确定。重要的是，我们最近 目前应用中的出版物和初步发现表明，肿瘤 微环境因素可能通过选择性地诱导Treg适应 上调FoxP3的脱泛素酶模块，包括USP21和USP22，但不包括USP7，以 控制Treg适应。目前提议的研究将确定肿瘤微环境。 诱导Tregs中USP21和USP22表达的因素(目标1)，并测试Tregs是否 由于同时缺失USP21和USP22不能适应恶劣的肿瘤微环境， 从而加强抗肿瘤免疫治疗(目标2)。我们建议的结果 研究将定义一种新的分子线索来控制Treg对肿瘤微环境和 为联合应用USP21和USP22抑制抗肿瘤免疫治疗提供理论依据。

Project Summary: One of the recent advances in cancer treatment is the development of immunotherapy largely through targeting the checkpoint receptors. However, attempts at immunotherapy to increase antitumor immune responses have achieved very limited success. A major hurdle in tumor immunotherapy is mediated by regulatory T (Treg) cells, which suppress the function of antitumor effector T cells. The lineage transcription factor Forkhead Box P3 (FoxP3) is known as a programmer for Treg adaptation in the harsh tumor microenvironment such as metabolic changes and hypoxia. However, the factors that control FoxP3-mediated Treg fitness to orchestrate the survival and functions of intratumoral Treg cells have not been identified. Importantly, our recent publications and preliminary discoveries in the current application suggest that tumor microenvironment factors possibly induce Treg fitness/adaptation through selectively upregulating a deubiquitinase module, including USP21 and USP22, but not USP7, of FoxP3 to control Treg adaptation. The current proposed studies will identify the tumor microenvironment factors that induce USP21 and USP22 expression in Tregs (Aim 1), and to test whether Tregs with simultaneous USP21 and USP22 deletion fail to adapt in the harsh tumor microenvironment, which consequently potentiates the antitumor immune therapy (Aim 2). Results from our proposed study will define a novel molecular cue in control Treg fitness to the tumor microenvironment and provide a rationale for the combined USP21 and USP22 suppression in antitumor immune therapy.