Figure 1. Model for TDO-derived kynurenine signaling through AHR. The tryptophan metabolite kynurenine is an endogenous ligand for the aryl hydrocarbon receptor (AHR) that can promote tumor cell growth, motility and immune escape.

Tryptophan (orange circle) enters the tumor cell and is degraded into kynurenine (purple circle) by tryptophan 2,3-dioxygenase (TDO2; TDO) [a(1)]. Kynurenine then binds to AHR (purple crescent), and the resulting ligand-receptor complex translocates into the nucleus [b(1)]. Within the nucleus, the complex forms a heterodimer with AHR nuclear translocator (ARNT; HIF1b) (blue square), which then interacts with dioxin-responsive elements (DREs) to regulate the expression of AHR target genes that promote tumor cell growth and motility [c(1)].

Tumor cells also can suppress the antitumor immune response through the release of TDO-derived kynurenine. Similar to what happens in tumor cells, kynurenine binds to AHR in immune cells [b(2)], translocates into the cell nucleus and forms a heterodimer with ARNT that regulates AHR target genes that promote immunosuppression [c(2)].

The identified pathways implicate TDO, kynurenine and AHR as potential therapeutic targets. (Figure based on Figure 5g in ref. 1.)