Oncotarget

Research Papers:

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

Holly C. Lewis, Raghavan Chinnadurai, Steven E. Bosinger and Jacques Galipeau _

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Oncotarget. 2017; 8:91914-91927. https://doi.org/10.18632/oncotarget.20166

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Abstract

Holly C. Lewis1, Raghavan Chinnadurai2, Steven E. Bosinger3,4 and Jacques Galipeau2

1Departments of Pediatrics and Hematology & Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

2Department of Medicine and University of Wisconsin Carbone Cancer Center, University of Wisconsin in Madison, Madison, WI, USA

3Department of Pathology & Laboratory Medicine, Emory University, Atlanta, GA, USA

4Yerkes NHP Genomics Core Laboratory, Div. Microbiology & Immunology, Yerkes National Primate Research Center, Atlanta, GA, USA

Correspondence to:

Jacques Galipeau, email: [email protected]

Keywords: MSC, AHR, IDO, 1-methyl tryptophan, cancer immunotherapy

Received: March 20, 2017    Accepted: July 02, 2017    Published: August 10, 2017

ABSTRACT

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-γ (IFN-γ) 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.


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