A deubiquitination module controls Treg adaptation to tumor microenvironment

项目摘要： 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 抗肿瘤免疫应答取得的成功非常有限。肿瘤治疗的主要障碍 免疫治疗是由调节性T（Treg）细胞介导的，其抑制抗肿瘤细胞的功能。 效应T细胞谱系转录因子叉头盒P3（FoxP 3）被称为转录因子。 Treg在苛刻的肿瘤微环境（如代谢变化）中的适应程序 和缺氧。然而，控制FoxP 3介导的Treg适应性以协调细胞增殖的因素是不确定的。 肿瘤内Treg细胞的存活和功能尚未确定。重要的是，我们最近 本申请中的出版物和初步发现表明， 微环境因素可能通过选择性地诱导Treg适应性/适应 上调FoxP 3的去泛素化酶模块，包括USP 21和USP 22，但不包括USP 7， 控制Treg适应。目前提出的研究将确定肿瘤微环境 诱导TGFAP中USP 21和USP 22表达的因子（目的1），并测试TGFAP是否 同时缺失USP 21和USP 22不能适应苛刻的肿瘤微环境， 从而增强抗肿瘤免疫治疗（目的2）。我们提出的结果 这项研究将定义一种新的分子线索，控制Treg对肿瘤微环境的适应性， 提供了在抗肿瘤免疫治疗中联合USP 21和USP 22抑制的依据。

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.