A deubiquitination module controls Treg adaptation to tumor microenvironment

去泛素化模块控制 Treg 对肿瘤微环境的适应

• 批准号: 10545001
• 负责人: Deyu Fang
• 金额: $ 55.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545001
• 关键词: Ablation; Acidity; Amino Acids; Antitumor Response; Cancer Patient; Carbon Dioxide; Clinical; Cues; Data; Deubiquitination; Development; FOXP3 gene; Glucose; Growth Factor; Human; Hypoxia; Immune system; Immunosuppression; Immunotherapy; Infiltration; Malignant neoplasm of lung; Mediating; Metabolic; Modeling; Molecular; Mus; Neoplasm Metastasis; Peptide Hydrolases; Publications; Regulatory T-Lymphocyte; Role; Stress; Testing; Therapeutic; Treatment Efficacy; Tumor Escape; Tumor Immunity; Ubiquitin; Up-Regulation; anti-tumor immune response; cancer cell; cancer therapy; checkpoint receptors; cytokine; effector T cell; fitness; forkhead protein; immune checkpoint blockade; immunogenicity; improved; neoplasm immunotherapy; neoplastic cell; novel; programs; success; synergism; transcription factor; tumor; tumor microenvironment; ubiquitin isopeptidase

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.

项目概要： 癌症治疗的最新进展之一是免疫疗法的发展 通过靶向检查点受体。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 免疫疗法由调节性 T (Treg) 细胞介导，可抑制抗肿瘤功能 效应T细胞。谱系转录因子 Forkhead Box P3 (FoxP3) 被称为 Treg 适应恶劣肿瘤微环境（例如代谢变化）的程序员 和缺氧。然而，控制 FoxP3 介导的 Treg 适应性以协调 肿瘤内 Treg 细胞的存活和功能尚未确定。重要的是，我们最近 当前申请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诱导Treg适应/适应 上调 FoxP3 的去泛素酶模块，包括 USP21 和 USP22，但不包括 USP7 控制Treg适应。目前提出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 同时删除 USP21 和 USP22 无法适应恶劣的肿瘤微环境， 从而增强抗肿瘤免疫治疗（目标 2）。我们提议的结果 研究将确定一种新的分子线索来控制 Treg 对肿瘤微环境的适应度 为抗肿瘤免疫治疗中联合抑制 USP21 和 USP22 提供了理论依据。