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.

STAT3/p53 pathway activation disrupts IFN-β–induced dormancy in tumor-repopulating cells

“…In contrast, less than 8% of CD133 -B16 cells could grow into colonies in the soft 3D fibrin gels, consistent with our previous report (30), suggesting that CD133 hi melanoma cells represent TRCs. Thus, in the following studies, we used in vitro culture-enriched and expanded melanoma TRCs to investigate the mechanistic aspects of how IFN-β induces stem-like melanoma cells into dormancy.…”

“…For conventional 2D cell culture, tumor cells were maintained in a rigid dish with complete culture medium. TRC culture was performed according to our previously published protocol (13,15,30) with some modification. In brief, fibrinogen (Searun Holdings Co.) was dissolved at -4°C overnight and, once completely dissolved, was diluted into 2 mg/ml with T7 buffer (pH 7.4, 50 mM Tris, 150 mM NaCl).…”

“…Whether SCLCCs can more readily enter dormancy by immune cues also remains unclear. We recently developed a mechanics-based method to select and amplify a minor population of tumor cells by culturing single tumor cells in soft 3D fibrin gels (13)(14)(15)(16)(17). The growing colonies showed spheroid-like morphological changes.…”

Interferon gamma in cancer immunotherapy

“…It is known that IFNγ signaling elicits apoptosis of differentiated tumor cells via STAT1. However, Liu and colleagues showed that IFNγ signaling resulted in IDO1/AhR‐dependent p27 induction when IDO1 and AhR were highly expressed in tumor‐repopulating cells (TRCs) . The p27 in turn bound to cytosolic pSTAT1, which prevented STAT1‐mediated tumor cell apoptosis.…”

IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape, and progression

“…IFN- γ mediated tumor dormancy can also be induced independent from STAT1 signaling. Tumor clones that highly express indolamine 2,3-dioxygenase 1 (IDO1) and kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) respond to IFN- γ by upregulating the cell cycle inhibitor p27, consequently preventing STAT1 signaling and inducing tumor dormancy [25]. In fact, p21 and p27 facilitate hypo-phosphorylation of the tumor suppressor Rb, thereby suppressing the activity of E2F transcription factor and inhibiting the activation of genes involved in cell proliferation.…”