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

• Published in: Nature communications Vol. 8; no. 1; p. 15207
• Main Authors: Liu, Yuying, Liang, Xiaoyu, Yin, Xiaonan, Lv, Jiadi, Tang, Ke, Ma, Jingwei, Ji, Tiantian, Zhang, Huafeng, Dong, Wenqian, Jin, Xun, Chen, Degao, Li, Yanchun, Zhang, Songyan, Xie, Heidi Q., Zhao, Bin, Zhao, Tong, Lu, Jinzhi, Hu, Zhuo-Wei, Cao, Xuetao, Qin, F. Xiao-Feng, Huang, Bo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 13/109; 13/31; 13/51; 13/89; 14/19; 38/77; 631/250/580/1884/2323; 631/67/580; 631/67/71; 96/1; 96/106; 96/2; Animals; Apoptosis - physiology; Cell Line, Tumor; Cell Proliferation - physiology; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Female; HEK293 Cells; Hep G2 Cells; Humanities and Social Sciences; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Interferon-gamma - immunology; Kynurenine - metabolism; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; multidisciplinary; Neoplasms - pathology; Receptors, Aryl Hydrocarbon - metabolism; Science; Science (multidisciplinary); STAT1 Transcription Factor - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15207

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. Tumour repopulating cells (TRC) are stem-like cells that can escape immune-mediated killing. Here, the authors show IFN-γ results in either dormancy or apoptosis of TRC depending on the activation of the IDO1 metabolic pathway, and that combining IFN-γ with IDO1 inhibitors results in enhanced tumour regression.