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.

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