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

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-? 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-? signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-? 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-?-induced dormancy but also results in enhanced repression of tumour growth by IFN-?-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-?, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-? and IDO/AhR inhibitors.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC5436221 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other