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

Author:

Liu Xinnan,Zhang Weiqi,Han Yichao,Cheng Hao,Liu Qi,Ke Shouyu,Zhu FangmingORCID,Lu Ying,Dai Xin,Wang Chuan,Huang GonghuaORCID,Su BingORCID,Zou Qiang,Li HuabingORCID,Zhao Wenyi,Xiao Lianbo,Lu Linrong,Tong XuemeiORCID,Pan FanORCID,Li HechengORCID,Li BinORCID

Abstract

AbstractTargeting 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.

Funder

National Natural Science Foundation of China

Publisher

Springer Science and Business Media LLC

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