Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

Yuying Liu, Xiaoyu Liang, Xiaonan Yin, Jiadi Lv, Ke Tang, Jingwei Ma, Tiantian Ji, Huafeng Zhang, Wenqian Dong, Xun Jin, Degao Chen, Yanchun Li, Songyan Zhang, Heidi Q. Xie, Bin Zhao, Tong Zhao, Jinzhi Lu, Zhuo-Wei Hu, Xuetao Cao, F. Xiao-Feng Qin and Bo Huang ()
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Yuying Liu: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Xiaoyu Liang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Xiaonan Yin: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Jiadi Lv: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Ke Tang: Tongji Medical College, Huazhong University of Science & Technology
Jingwei Ma: Tongji Medical College, Huazhong University of Science & Technology
Tiantian Ji: Tongji Medical College, Huazhong University of Science & Technology
Huafeng Zhang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Wenqian Dong: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Xun Jin: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Degao Chen: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Yanchun Li: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Songyan Zhang: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
Heidi Q. Xie: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
Bin Zhao: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences
Tong Zhao: Institute of Microbiology, Chinese Academy of Sciences
Jinzhi Lu: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
Zhuo-Wei Hu: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Xuetao Cao: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences
F. Xiao-Feng Qin: Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College
Bo Huang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-γ induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-γ signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-γ results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-γ-induced dormancy but also results in enhanced repression of tumour growth by IFN-γ-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-γ, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-γ and IDO/AhR inhibitors.

Date: 2017
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DOI: 10.1038/ncomms15207

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