An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Abstract

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO–AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology. The tryptophan catabolite kynurenine (Kyn) and tryptophan degradation by indoleamine-2,3-dioxygenases have previously been implicated in suppressing an antitumour immune response. Michael Platten and colleagues now identify tryptophan-2,3-dioxygenase (TDO) as the enzyme expressed in gliomas and other cancers that converts tryptophan to Kyn. Kyn is an endogenous ligand for the aryl hydrocarbon receptor (AHR), acting directly on glioma cells to promote tumorigenesis. TDO expression in cancer cells also suppresses an AHR-mediated immune response. In human glioblastomas, the expression of TDO and AHR-regulated genes are associated with more advanced stages and poorer clinical outcome.