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FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity

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机构： [1]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2]Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [3]Center for Cancer Immunology Research, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China. [4]Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [5]Department of Gastrointestinal Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [6]Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. [7]Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China. [8]Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China. [9]Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [10]Department of Obstetrics and Gynecology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China. [11]Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, China. [12]Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China. [13]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China. [14]Department of Oncology, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [15]Department of Integrated TCM & Western Medicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.

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Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.© 2024. The Author(s).

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出版当年[2023]版：

大类 | 1 区

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第一作者机构： [1]Center for Immune-Related Diseases at Shanghai Institute of Immunology, 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： [1]Center for Immune-Related Diseases at Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [2]Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [9]Institute of Arthritis Research, Guanghua Integrative Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [13]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China. [14]Department of Oncology, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [15]Department of Integrated TCM & Western Medicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.

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