The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells

The catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is a key step in tolerance effected by a variety of cell types, including mesenchymal stromal cells (MSCs). Trp catabolism generates molecules known as kynurenines, whose tolerance mechanisms involve activation of the Aryl Hydrocarbon Receptor (AHR). A synthetic analog of Trp, 1-methyl tryptophan (1MT), is a selective inhibitor of IDO enzymatic activity being utilized in cancer immunotherapy trials. We hypothesized 1MT might activate AHR independently of its effects on IDO. We demonstrate MSCs express AHR protein, and that in vitro treatment with 1MT causes AHR nucleotranslocation. Upon analyzing mRNA, we observed transcriptional upregulation of cytochrome p450 1a1 and 1b1 by 1MT racemic mixture (R-MT), consistent with AHR-activation. RNA-sequencing identified Nrf2, MAPK12 and IL-1a as downstream targets of 1MT. We demonstrate 1a1 and 1b1 activation by 1MT in IDO+ MSC following interferon-gamma (IFN-gamma) activation, suggesting AHR signaling is uncoupled from IDO catalytic function. Such a mechanism of action for 1MT may extend its usage to a wider range of patients, irrespective of tumor IDO expression. These observations support a novel paradigm by which AHR-activating compounds like 1MT can be used in cancer immunotherapy to stimulate a pro-inflammatory response.