Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes.

Autor:	Solvay M; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Holfelder P; Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.; DKTK Division of Metabolic Crosstalk in Cancer, German Cancer Research Center, DKFZ, INF 280, 69120 Heidelberg, Germany., Klaessens S; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Pilotte L; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Stroobant V; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Lamy J; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Naulaerts S; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Spillier Q; Louvain Drug Research Institute, UCLouvain, Brussels, Belgium., Frédérick R; Louvain Drug Research Institute, UCLouvain, Brussels, Belgium., De Plaen E; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Sers C; Partner Site Berlin, German Cancer Consortium, Heidelberg, Germany.; German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany., Opitz CA; DKTK Division of Metabolic Crosstalk in Cancer, German Cancer Research Center, DKFZ, INF 280, 69120 Heidelberg, Germany.; Neurology Clinic and National Center for Tumor Diseases, Heidelberg, Germany., Van den Eynde BJ; de Duve Institute, UCLouvain, Brussels, Belgium.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium., Zhu J; de Duve Institute, UCLouvain, Brussels, Belgium jingjng.zhu@uclouvain.be.; Ludwig Institute for Cancer Research, de Duve Institute, Brussels, Belgium.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Jun; Vol. 11 (6).
DOI:	10.1136/jitc-2023-006728
Abstrakt:	Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan-dioxygenase (TDO) are enzymes catabolizing the essential amino acid tryptophan into kynurenine. Expression of these enzymes is frequently observed in advanced-stage cancers and is associated with poor disease prognosis and immune suppression. Mechanistically, the respective roles of tryptophan shortage and kynurenine production in suppressing immunity remain unclear. Kynurenine was proposed as an endogenous ligand for the aryl hydrocarbon receptor (AHR), which can regulate inflammation and immunity. However, controversy remains regarding the role of AHR in IDO1/TDO-mediated immune suppression, as well as the involvement of kynurenine. In this study, we aimed to clarify the link between IDO1/TDO expression, AHR pathway activation and immune suppression. Methods: AHR expression and activation was analyzed by RT-qPCR and western blot analysis in cells engineered to express IDO1/TDO, or cultured in medium mimicking tryptophan catabolism by IDO1/TDO. In vitro differentiation of naïve CD4 + T cells into regulatory T cells (Tregs) was compared in T cells isolated from mice bearing different Ahr alleles or a knockout of Ahr , and cultured in medium with or without tryptophan and kynurenine. Results: We confirmed that IDO1/TDO expression activated AHR in HEK-293-E cells, as measured by the induction of AHR target genes. Unexpectedly, AHR was also overexpressed on IDO1/TDO expression. AHR overexpression did not depend on kynurenine but was triggered by tryptophan deprivation. Multiple human tumor cell lines overexpressed AHR on tryptophan deprivation. AHR overexpression was not dependent on general control non-derepressible 2 (GCN2), and strongly sensitized the AHR pathway. As a result, kynurenine and other tryptophan catabolites, which are weak AHR agonists in normal conditions, strongly induced AHR target genes in tryptophan-depleted conditions. Tryptophan depletion also increased kynurenine uptake by increasing SLC7A5 (LAT1) expression in a GCN2-dependent manner. Tryptophan deprivation potentiated Treg differentiation from naïve CD4 + T cells isolated from mice bearing an AHR allele of weak affinity similar to the human AHR. Conclusions: Tryptophan deprivation sensitizes the AHR pathway by inducing AHR overexpression and increasing cellular kynurenine uptake. As a result, tryptophan catabolites such as kynurenine more potently activate AHR, and Treg differentiation is promoted. Our results propose a molecular explanation for the combined roles of tryptophan deprivation and kynurenine production in mediating IDO1/TDO-induced immune suppression. Competing Interests: Competing interests: CAO is founder and managing director of cAHRmeleon Bioscience. CAO has patents on AHR inhibitors in cancer (WO2013034685); a method to multiplex tryptophan and its metabolites (WO2017072368); a transcriptional signature to determine AHR activity (WO2020201825); Interleukin-4-induced gene 1 (IL4I1) as a biomarker (WO2020208190) Interleukin-4-induced gene 1 (il4i1) and its metabolites as biomarkers for cancer (WO2021116357). BJVdE is cofounder of iTeos Therapeutics. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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