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

Xinnan Liu, Weiqi Zhang, Yichao Han, Hao Cheng, Qi Liu, Shouyu Ke, Fangming Zhu, Ying Lu, Xin Dai, Chuan Wang, Gonghua Huang, Bing Su, Qiang Zou, Huabing Li, Wenyi Zhao, Lianbo Xiao, Linrong Lu, Xuemei Tong, Fan Pan (), Hecheng Li () and Bin Li ()
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Xinnan Liu: Shanghai Jiao Tong University School of Medicine
Weiqi Zhang: Shanghai Jiao Tong University School of Medicine
Yichao Han: Shanghai Jiao Tong University School of Medicine
Hao Cheng: Chinese Academy of Sciences
Qi Liu: Shanghai Jiao Tong University School of Medicine
Shouyu Ke: Shanghai Jiao Tong University School of Medicine
Fangming Zhu: University of Alabama at Birmingham
Ying Lu: Shanghai Medical College of Fudan University
Xin Dai: Harbin Medical University Cancer Hospital
Chuan Wang: Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Gonghua Huang: Shanghai Jiao Tong University School of Medicine
Bing Su: Shanghai Jiao Tong University School of Medicine
Qiang Zou: Shanghai Jiao Tong University School of Medicine
Huabing Li: Shanghai Jiao Tong University School of Medicine
Wenyi Zhao: Shanghai Jiao Tong University School of Medicine
Lianbo Xiao: Shanghai University of Traditional Chinese Medicine
Linrong Lu: Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital
Xuemei Tong: Shanghai Jiao Tong University School of Medicine
Fan Pan: Chinese Academy of Sciences
Hecheng Li: Shanghai Jiao Tong University School of Medicine
Bin Li: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44391-9

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