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.
View: Text | PDF
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

×

Figure 7

IFN-β/AhR blockade improves survival in vivo.

Options: View larger image (or click on image) Download as PowerPoint
IFN-β/AhR blockade improves survival in vivo. (A) Mice with 5 × 5 mm B16...
(A) Mice with 5 × 5 mm B16 melanoma were treated with IFN-β daily for 3 days. IDO1, AhR, p27, p-STAT3 (Y), p-STAT3 (S), and STAT3 were analyzed by Western blot in tumor cells (n = 5). (B) As in A, but tumor tissue was immunostained with anti-AhR, S100, and p-STAT3 (S), and DAPI. The percentage of cells with AhR nuclear localization was determined among 500 S100+ cells in 10 nonconsecutive sections (upper right panel). The number of cells with both AhR and p-STAT3 (S) nuclear localization was counted (lower right panel) (n = 5). Scale bars: 10 μm. (C) Mice with 7 × 7 mm B16 melanoma were treated with IFN-β, IFN-β/1-MT, or IFN-β/DMF for 8 days. CD133hi tumor cells isolated were seeded in soft 3D fibrin gels. Colony number was counted on day 4 (n = 5). (D and E) Mice were inoculated with 1 × 105 unsorted B16 cells. When tumor size was 7 × 7 mm, mice were treated with IFN-β, 1-MT, or IFN-β/1-MT (D) or IFN-β, DMF, or IFN-β/DMF (E) for 10 days. Tumor growth was measured and long-term survival was analyzed (n = 10). (F and G) NOD-SCID mice with 7 × 7 mm A375 melanoma were treated with IFN-β, 1-MT, or IFN-β/1-MT (F) (n = 8) or IFN-β, DMF, or IFN-β /DMF (G) for 10 days (n = 8). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 and ##P < 0.01 vs. IFN-β–treated group, by 2-tailed Student’s t test (B), 1-way ANOVA (C–G, left panels of D and E), and Kaplan-Meier survival analysis (D and E, right panels).