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Nat Commun. 2017 May 10;8:15207. doi: 10.1038/ncomms15207.

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

Author information

1
National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China.
2
Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
3
Department of Biochemistry &Molecular Biology, Tongji Medical College, Huazhong University of Science &Technology, Wuhan 430030, China.
4
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
5
Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
6
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, Beijing 100050, China.
7
Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100005, China.
8
Suzhou Institute of Systems Medicine, Suzhou 215123, China.

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.

PMID:
28488695
PMCID:
PMC5436221
DOI:
10.1038/ncomms15207
[Indexed for MEDLINE]
Free PMC Article

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