STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells
Yuying Liu, … , F. Xiao-Feng Qin, Bo Huang
Yuying Liu, … , F. Xiao-Feng Qin, Bo Huang
Published February 12, 2018
Citation Information: J Clin Invest. 2018;128(3):1057-1073. https://doi.org/10.1172/JCI96329.
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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 5

Nuclear translocation of p-STAT3 (S) mediates TRC apoptosis by IFN-β/AhR blockade.

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Nuclear translocation of p-STAT3 (S) mediates TRC apoptosis by IFN-β/AhR...
(A) B16 TRCs with or without STAT3 knockout were treated with PBS, IFN-β, IFN-β/1-MT, or IFN-β/DMF. Apoptosis was analyzed by flow cytometry. (B) p-STAT3 (Y) and STAT3 were determined by Western blot in B16 TRCs treated with IFN-β or IFN-β/DMF. (C) Western blot analysis of p-STAT3 (Y) and STAT3 in B16 TRCs treated with PBS or Kyn, Vec-B16 TRCs, or IDO1-B16 TRCs. (D) Western blot analysis of p-Src and Src from B16 cells, B16 TRCs, IDO1-overexpressing B16 TRCs, B16 TRCs treated with PBS, IFN-β, Kyn, or IFN-β/DMF. (E) ChIP-qPCR analysis was performed with anti-AhR and primers specific for Src in IFN-β–pretreated B16 TRCs. (F) Western blot analysis of p-Src and Src in B16 TRCs treated with PBS, IFN-β, IFN-β/1-MT, or IFN-β/DMF. (G) p-STAT3 (Y) and DAPI immunostaining in IFN-β–treated B16 TRCs. Scale bar: 10 μm. (H) Western blot analysis of p-STAT3 (S) and STAT3 in B16 TRCs treated with IFN-β. (I) As in G, B16 TRCs were immunostained against p-STAT3 (S) and DAPI. Scale bar: 10 μm. (J) B16 TRCs were treated with IFN-β or PBS. Cytosolic and nuclear p-STAT3 (Y), p-STAT3 (S), and STAT3 were analyzed. (K) B16 TRCs were transfected with Flag-WT-STAT3, Flag-Y705F-STAT3, or Flag-S727A-STAT3 and then treated with IFN-β for 24 hours. Flag and DAPI were visualized by immunostaining. Scale bar: 5 μm. (L) Same conditions as in F. The expression of p-STAT3 (Y), p-STAT3 (S), and STAT3 were analyzed by Western blot. Graphs represent mean ± SEM of 3 assays. **P < 0.01, by 1-way ANOVA (A) and 2-tailed Student’s t test (E).