IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation

• Published in: Frontiers in immunology 2021-04, Vol.12, p.678999
• Main Authors: Amobi-McCloud, Adaobi, Muthuswamy, Ravikumar, Battaglia, Sebastiano, Yu, Han, Liu, Tao, Wang, Jianmin, Putluri, Vasanta, Singh, Prashant K, Qian, Feng, Huang, Ruea-Yea, Putluri, Nagireddy, Tsuji, Takemasa, Lugade, Amit A, Liu, Song, Odunsi, Kunle
• Format: Article
• Language: English
• Subjects: 3-dioxygenase; AhR (aryl hydrocarbon Receptor); Animals; Binding Sites; Biomarkers; Disease Models, Animal; Disease Susceptibility; Female; Gene Expression Regulation, Neoplastic; Humans; IDO; Immunology; indoleamine 2; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; KYN; kynurenine; Male; Mice; Ovarian Neoplasms - etiology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Programmed Cell Death 1 Receptor - chemistry; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Protein Binding; Receptors, Aryl Hydrocarbon - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.678999

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.