Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-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-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.

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Cited by papers we hold 9

• Dual regulation of gastrointestinal tumor progression by the IFN-γ/STAT1 pathway and prospects for targeted therapy · 2025
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• Nanog mediated by FAO/ACLY signaling induces cellular dormancy in colorectal cancer cells · 2022
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• Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response · 2022
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• Exploring immunotherapy in colorectal cancer · 2022
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• Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy · 2021
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• IDO Expression in Cancer: Different Compartment, Different Functionality? · 2020
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• Stem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance · 2019
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• Interferon gamma in cancer immunotherapy · 2018
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• The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy · 2018
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