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 Lü, Xin Dai, Chuan Wang, Gonghua Huang, Bing Su, Qiang Zou, Huabing Li, Wenyi Zhao, Lianbo Xiao, Linrong Lu, Xuemei Tong, Fan Pan, Hecheng Li, Bin Li, Hecheng Li, Bin Li
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.