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 March 1, 2018; First 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 Stem cells

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 1

IFN-β induces TRC dormancy in vivo.

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IFN-β induces TRC dormancy in vivo. (A) C57BL/6 mice with 5 × 5 mm B16 m...
(A) C57BL/6 mice with 5 × 5 mm B16 melanoma were intratumorally treated with 250 ng IFN-β once per day for 3 days. Isolated tumor cells were assayed for cell-cycle analysis (n = 5). (B) As in A, but some mice were treated with 10 μg IFN-γ + TNF-α for 3 days as positive control. Isolated tumor cells were stained with SA–β-gal (n = 5). (C and D) As in A, but CD133hi tumor cells were counted by flow cytometry (C) (n = 5), and the cell cycle of CD133hi tumor cells was analyzed (D) (n = 5). (E) B16 TRCs (5 × 103) were s.c. injected into mice. On day 3, 50 ng IFN-β was injected into the tumor site once every 2 days. On days 5, 10, and 20, tumor cell–injected tissues were analyzed by immunostaining against S100β or H&E staining. Tumor size is presented photographically (left) and graphically (right) (n = 6). Scale bars: 50 μm. (F) Mice subcutaneously injected with 5 × 103 B16 TRCs were intratumorally treated with IFN-β (50 ng/d) for 10 days and then further treated with IFN-β or IFN-β + anti–IFN-β antibody once every 2 days for 5 days. Tissues at the injection site were used for immunostaining for S100β and stained with H&E (n = 6). Scale bars: 50 μm. (G) The same as E, except that at day 20, tissues with tumor cell inoculation were immunostained with anti-NR2F1, -Ki67, and DAPI (n = 5). Scale bar: 10 μm. Data represent mean ± SEM. **P < 0.01, 2-tailed Student’s t test (A, D, and G) and 1-way ANOVA (E and F).