TY - JOUR
T1 - IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation
AU - Amobi-McCloud, Adaobi
AU - Muthuswamy, Ravikumar
AU - Battaglia, Sebastiano
AU - Yu, Han
AU - Liu, Tao
AU - Wang, Jianmin
AU - Putluri, Vasanta
AU - Singh, Prashant K.
AU - Qian, Feng
AU - Huang, Ruea Yea
AU - Putluri, Nagireddy
AU - Tsuji, Takemasa
AU - Lugade, Amit A.
AU - Liu, Song
AU - Odunsi, Kunle
N1 - Publisher Copyright:
© Copyright © 2021 Amobi-McCloud, Muthuswamy, Battaglia, Yu, Liu, Wang, Putluri, Singh, Qian, Huang, Putluri, Tsuji, Lugade, Liu and Odunsi.
PY - 2021/4/16
Y1 - 2021/4/16
N2 - 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.
AB - 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.
KW - 3-dioxygenase
KW - AhR (aryl hydrocarbon Receptor)
KW - IDO
KW - immunosuppression
KW - indoleamine 2
KW - KYN
KW - kynurenine
KW - PD-1
UR - https://www.scopus.com/pages/publications/85105237678
U2 - 10.3389/fimmu.2021.678999
DO - 10.3389/fimmu.2021.678999
M3 - Article
C2 - 34025677
AN - SCOPUS:85105237678
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 678999
ER -