Major Finding: Kyn is an endogenous ligand of AHR that is generated by TDO in tumors.
Impact: Kyn-dependent AHR activation promotes tumor growth and immunosuppression.
Clinical Relevance: TDO and AHR may be promising therapeutic targets for glioma therapy.
Activation of the aryl hydrocarbon receptor (AHR) caused by exposure to toxic environmental xenobiotics has been implicated in carcinogenesis and immune suppression, but a mechanistic link between these 2 phenomena has been lacking. Further, no endogenous ligand capable of activating the AHR has been identified in a physiologically relevant disease setting. Opitz and colleagues report the surprising discovery that kynurenine (Kyn), a catabolite of tryptophan (Trp) excessively produced by glioma cells, binds and activates the AHR. They show that glioma cells release high micromolar amounts of Kyn due to specific overexpression of tryptophan-2,3-dioxygenase (TDO), an enzyme normally expressed in the liver that regulates systemic Trp levels. Glioma sections with high TDO expression displayed decreased immune cell infiltration, which the authors linked to Kyn-dependent inhibition of T-cell proliferation. Kyn was also shown to promote the survival and motility of glioma cells, and microarray and pathway analyses revealed that the most highly Kyn-induced genes were all regulated by the AHR. AHR was required for both the autocrine effect of Kyn on glioma cell growth and motility and the paracrine effect on T-cells in TDO-expressing glioma xenografts. In primary human gliomas, TDO expression was correlated with AHR and AHR target gene expression, and Kyn-dependent expression of AHR gene targets predicted poor survival in glioma. Collectively, these findings identify a mechanism of endogenous AHR activation by constitutive Trp catabolism and suggest that the TDO-Kyn-AHR signaling pathway is an important mediator of tumor growth and immune suppression.
Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011;478:197–203.
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