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Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine.
- Source :
-
Nature communications [Nat Commun] 2020 Aug 11; Vol. 11 (1), pp. 4011. Date of Electronic Publication: 2020 Aug 11. - Publication Year :
- 2020
-
Abstract
- Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8 <superscript>+</superscript> T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.
- Subjects :
- Animals
Drug Resistance, Neoplasm
Humans
Immune Tolerance
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Mice
Neoplasms immunology
Neoplasms therapy
Programmed Cell Death 1 Receptor antagonists & inhibitors
Programmed Cell Death 1 Receptor immunology
Receptors, Aryl Hydrocarbon genetics
Receptors, Aryl Hydrocarbon metabolism
Signal Transduction
Tryptophan Oxygenase genetics
Tryptophan Oxygenase metabolism
Tumor Cells, Cultured
Tumor Microenvironment
Kynurenine immunology
Macrophages immunology
Receptors, Aryl Hydrocarbon antagonists & inhibitors
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 32782249
- Full Text :
- https://doi.org/10.1038/s41467-020-17750-z