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IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation
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IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation
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Journal Article
IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation
2021
Overview
The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1 + CD8 + tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.
Publisher
Frontiers Media SA,Frontiers Media S.A
Subject
/ AhR (aryl hydrocarbon Receptor)
/ Animals
/ Enzymes
/ Female
/ Gene Expression Regulation, Neoplastic
/ Genes
/ Genomes
/ Humans
/ IDO
/ Immune checkpoint inhibitors
/ Immunity
/ Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics
/ Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism
/ Kinases
/ KYN
/ Male
/ Mice
/ Ovarian Neoplasms - etiology
/ Ovarian Neoplasms - metabolism
/ Ovarian Neoplasms - pathology
/ Patients
/ Programmed Cell Death 1 Receptor - chemistry
/ Programmed Cell Death 1 Receptor - genetics
/ Programmed Cell Death 1 Receptor - metabolism
/ Receptors, Aryl Hydrocarbon - metabolism
/ T-Lymphocyte Subsets - immunology
/ T-Lymphocyte Subsets - metabolism
/ Tumors
