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 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 8

IDO/AhR blockade disrupts dormancy of primary human TRCs.

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IDO/AhR blockade disrupts dormancy of primary human TRCs. (A) Primary hu...
(A) Primary human melanoma cells after 2 days culture in soft 3D fibrin gels were treated with IFN-β (10 ng/ml) for the indicated days (n = 3). (B and C) Primary human melanoma TRCs (n = 3) after 3 days IFN-β treatment were subjected to cell-cycle analysis (B) or immunostaining of NR2F1 and Ki67 (C). (D) Same as B, but some cells were subjected to Western blot against IDO1 and AhR (left) or immunostaining with anti-AhR (red) and DAPI (right) (n = 3). (E) NOD-SCID mice with 7 × 7 mm melanoma by s.c. injection of primary human TRCs were treated with IFN-β/1-MT or IFN-β/DMF for 10 days. Tumor growth was measured (n = 8). (F) IFN-β expression in various human cancers from the NIH TCGA (The Cancer Genome Atlas) database, including colon (638 TCGA entries), stomach (375 TCGA entries), breast (414 TCGA entries), urothelial (531 TCGA entries), lung (1033 TCGA entries), pancreatic (177 TCGA entries) cancers, and melanoma (472 TCGA entries), was analyzed according to the formula IFN-β = log2(FPKM + 1), where FPKM indicates fragments per kb of transcript per million mapped reads. (G) Representatives of immunohistochemical staining IFN-β from 10 melanoma patient samples (upper panels). Immunostaining intensity was quantified (lower panel) relative to the no. 1 patient, which was defined as 1. Patient samples with a calculated relative intensity greater than 10 were considered IFN-βhi, while patient samples with a calculated relative intensity less than 10 were defined as IFN-βlo. (H) Immunostaining of NR2F1 and Ki67 in IFN-βhi and IFN-βlo patients with melanoma (n = 2). The percentage of NR2F1+Ki67– or NR2F1–Ki67+ cells was calculated. (I) Correlation between IFN-β expression and melanoma patients’ survival. (J) Schematic diagram showing the signaling pathway involved in IFN-β–induced TRC dormancy. Data represent mean ± SEM. **P < 0.01, by 2-tailed Student’s t test (A–C, G, and H), 1-way ANOVA (E), and Kaplan-Meier survival analysis (I). Scale bars: 50 μm (A and G); 10 μm (C, D, and H).