Figure 1.

The immunosuppressive functions of IDO1/TDO-mediated tryptophan catabolism. Extrahepatic and hepatic cells express indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) to consume tryptophan and give rise to numerous bioactive metabolites such as kynurenine. Elevated expression of IDO1 or TDO, such as in cancer, increases the relative kynurenine levels while reducing tryptophan content. Kynurenine enters cells via System L transporters. (A) Increased kynurenine levels inhibit proliferation of T-cells and natural killer (NK) cells by interacting with aryl hydrocarbon receptor (AhR) to express programmed cell death protein 1 (PD-1). Previous studies have suggested the involvement of the general control non-deprepressible-2 (GCN2) kinase and mammalian target of rapamycin (mTOR) in proliferation inhibition but the exact mechanism through which this occurs still remains unresolved. (B) Kynurenine induces differentiation of naïve CD4⁺ T-cells to immunosuppressive T-regulatory cells by activation of AhR and induction of the FoxP3 transcription factor. Taken together, an immune suppressed tumour microenvironment is created that promotes survival of cancer cells.