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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Female
  • HEK293 Cells
  • Hep G2 Cells
  • 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
  • Neoplasms / pathology*
  • Receptors, Aryl Hydrocarbon / metabolism*
  • STAT1 Transcription Factor / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • IFNG protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Receptors, Aryl Hydrocarbon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Kynurenine
  • Interferon-gamma