Image_3_IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation.tif
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.
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References
- https://doi.org//10.3322/caac.21456
- https://doi.org//10.7150/jca.7810
- https://doi.org//10.1016/S1470-2045(19)30285-2
- https://doi.org//10.1073/pnas.0509182102
- https://doi.org//10.1056/NEJMoa020177
- https://doi.org//10.1001/jamaoncol.2017.3290
- https://doi.org//10.4049/jimmunol.168.8.3771
- https://doi.org//10.1016/j.immuni.2005.03.013
- https://doi.org//10.1038/ni.1915
- https://doi.org//10.4049/jimmunol.0903670
- https://doi.org//10.1158/0008-5472.CAN-08-2106
- https://doi.org//10.1016/j.ygyno.2009.07.015
- https://doi.org//10.1158/1078-0432.CCR-04-2671
- https://doi.org//10.3892/or.17.6.1333
- https://doi.org//10.1007/s00262-012-1265-x
- https://doi.org//10.1084/jem.20130066
- https://doi.org//10.1016/j.ygyno.2017.07.005
- https://doi.org//10.2139/ssrn.3327362
- https://doi.org//10.1038/nrd.2018.67
- https://doi.org//10.1007/s00281-018-0702-0
- https://doi.org//10.1073/pnas.1003345107
- https://doi.org//10.1038/nature10491
- https://doi.org//10.18632/oncotarget.4751
- https://doi.org//10.1093/carcin/21.4.585
- https://doi.org//10.1158/1940-6207.CAPR-18-0201
- https://doi.org//10.1177/1178646917691938
- https://doi.org//10.1016/j.bbamcr.2010.02.007
- https://doi.org//10.4049/jimmunol.176.11.6752
- https://doi.org//10.1016/j.ymeth.2019.01.018
- https://doi.org//10.1038/ni735
- https://doi.org//10.1016/j.it.2016.01.004
- https://doi.org//10.1158/0008-5472.CAN-11-1792
- https://doi.org//10.1124/mol.109.061788
- https://doi.org//10.1146/annurev.pharmtox.39.1.103
- https://doi.org//10.1016/j.bbrc.2007.10.140
- https://doi.org//10.1126/science.256.5060.1193
- https://doi.org//10.1038/nmeth.2688
- https://doi.org//10.1093/toxsci/kfq217
- https://doi.org//10.1038/nm934
- https://doi.org//10.1016/j.ccell.2018.02.005
- https://doi.org//10.1038/ncomms6101
- https://doi.org//10.1016/j.it.2015.11.007
- https://doi.org//10.3892/ijmm.2018.3624
- https://doi.org//10.1172/JCI70712
- https://doi.org//10.1158/0008-5472.CAN-10-1843
- https://doi.org//10.4049/jimmunol.0903519
- https://doi.org//10.1158/1078-0432.CCR-18-1515
- https://doi.org//10.1093/bioinformatics/btq418
- https://doi.org//10.1002/0471142727.mb2129s109
- https://doi.org//10.1002/0471250953.bi0206s21
- https://doi.org//10.1093/nar/28.1.27
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Categories
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity