Open AccessBlockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells
Author(s) -
Yuying Liu,
Xiaoyu Liang,
Xiaonan Yin,
Jiadi Lv,
Ke Tang,
Jingwei Ma,
Tiantian Ji,
Huafeng Zhang,
Wenting Dong,
Xun Jin,
Degao Chen,
Yanchun Li,
Songyan Zhang,
Heidi Qunhui Xie,
Bin Zhao,
Tong Zhao,
Jinzhi Lu,
Zhuo Wei Hu,
Xuetao Cao,
F. Xiao-Feng Qin,
Bo Huang
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms15207
Subject(s) - aryl hydrocarbon receptor , microbiology and biotechnology , cancer research , indoleamine 2,3 dioxygenase , biology , apoptosis , immune system , stat1 , dormancy , kynurenine , in vivo , signal transduction , chemistry , immunology , biochemistry , transcription factor , genetics , tryptophan , botany , germination , amino acid , gene
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.