IDO1‐mediated Trp‐kynurenine‐AhR signal activation induces stemness and tumor dormancy in oral squamous cell carcinomas

The non‐proliferative residual tumor cells in cancer therapeutics are considered tumor‐repopulating cells (TRCs) and a major issue for tumor recurrences and distant metastases. TRCs are stem cell‐like cancer cells repopulating tumors and associating with immune‐mediated tumor dormancy. Cell cycle arrest is also coupled to a tumor‐initiating or pluripotent capacity. INF‐γ, a cytokine with an anti‐tumor effect, also acts as an inhibitory effect on the cancer immune response via the induction of PD‐L1 on the surface of cancer cells. The anti‐tumor immune response may shift TRCs from proliferation to dormancy by a specific mechanism. Indoleamine 2, 3‐dioxygenase 1 (IDO1) is a metabolic enzyme to produce kynurenine (KYN) from tryptophan (Trp) and is expressed in cancer cells and dendritic cells in the immune system. IDO1 plays an important role for cancer cells to evade the attack from the activated CTLs. Recently, the signaling from the interaction between KYN and aryl hydrocarbon receptor (AhR), a dioxin receptor, has been reported to induce cancer cell dormancy. However, it is currently unclear what is the immune mechanism for the entry of tumor into dormancy and how stemness is coupled to the tumor cell arrest. In this study, we revealed that IDO1 induced by IFN‐γ activated Trp‐KYN‐AhR signaling and induced stemness in OSCC cells contributing to the entry of tumor into dormancy. In this mechanism, it was suggested that STAT1 was a key regulator between tumor differentiation and tumor dormancy. The regulation of IDO1‐mediated Trp‐KYN‐AhR signal activation could provide a new strategy for the cancer treatment.