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Gallic acid induces T-helper-1-like Treg cells and strengthens immune checkpoint blockade efficacy

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机构： [1]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2]Department of Medical Oncology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China. [3]Shanghai Affinity Biopharmaceutical Co., Ltd, Shanghai, China. [4]Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China. [5]Department of Thoracic Surgery, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [6]Fudan University School of Basic Medical Sciences, Shanghai, China. [7]Unit of Immune and Metabolic Regulation, School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [8]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China binli@shsmu.edu.cn. [9]Department of Thoracic Surgery, Clinical Translational Research Center, Shanghai Pulmonary Hospital, Shanghai, China. [10]Department of Integrated TCM and Western Medicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. [11]Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [12]Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Shenzhen, Guangdong, China.

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Foxp3+ regulatory T (Treg) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting Treg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers.We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and Treg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in Treg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy.Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of Treg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen Treg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8+ T cells' production of IFN-γ and limited tumor growth.Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3lo Treg cells.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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出版当年[2021]版：

大类 | 2 区医学

小类 | 2 区肿瘤学 2 区免疫学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区免疫学 2 区肿瘤学

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出版当年[2020]版：

Q1 IMMUNOLOGY Q1 ONCOLOGY

最新[2023]版：

Q1 IMMUNOLOGY Q1 ONCOLOGY

影响因子： 10.3 最新[2023版] 11.6 最新五年平均 13.751 出版当年[2020版] 13.864 出版当年五年平均 10.252 出版前一年[2019版] 12.485 出版后一年[2021版]

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第一作者机构： [1]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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通讯作者：

通讯机构： [8]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Respiratory and Critical Care Medicine of Ruijin Hospital, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China binli@shsmu.edu.cn. [9]Department of Thoracic Surgery, Clinical Translational Research Center, Shanghai Pulmonary Hospital, Shanghai, China. [10]Department of Integrated TCM and Western Medicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. [11]Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [12]Shenzhen Key Laboratory of Immunity and Inflammatory Diseases, Shenzhen, Guangdong, China.

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