STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells
Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang
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Research Article Immunology

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

Abstract

Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell–intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-β treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/aryl hydrocarbon receptor/p27–dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-β signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-β correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-β provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities.

Authors

Yuying Liu, Jiadi Lv, Jinyan Liu, Xiaoyu Liang, Xun Jin, Jing Xie, Le Zhang, Degao Chen, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Qingzhu Jia, Bo Zhu, Yan Kong, Jun Guo, Haizeng Zhang, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin, Bo Huang

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Figure 2

IFN-β induces TRC dormancy in vitro.

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IFN-β induces TRC dormancy in vitro. (A and B) B16 or A375 TRCs seeded i...
(A and B) B16 or A375 TRCs seeded in soft 3D fibrin gels were cultured for 2 days and then treated with different doses of IFN-β for an additional 2 days (d2) or 4 days. In another setting, IFN-β was removed from day 4 and the colonies were measured on day 6. Colony size was indicated (A), and cell cycle was analyzed after 3 days of IFN-β treatment (5 ng/ml) (B). Scale bars: 50 μm. (C) The same as B, but immunostaining of NR2F1/Ki67 or DEC2/Ki67 was performed. Scale bars: 10 μm. (D) IFN-β treatment decreased glucose (Glu) consumption in B16 or A375 TRCs. (E) B16 or A375 TRCs were treated with IFN-β or IFN-γ/TNF-α for 72 hours. SA–β-gal staining was conducted. (F) B16 TRCs, A375 TRCs, or dormant B16 or A375 TRCs (48 hours IFN-β treatment) were treated with cisplatin (Cis) (3 μg/ml), MTX (2 μg/ml), or PAX (3 μg/ml) for 24 hours. Cell viability was measured by flow cytometry. Graphs represent mean ± SEM of 3 independent experiments. *P < 0.05; **P < 0.01, 1-way ANOVA (A and E) and 2-tailed Student’s t test (B–D and F).