Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine Journal Article
| Authors: | Campesato, L. F.; Budhu, S.; Tchaicha, J.; Weng, C. H.; Gigoux, M.; Cohen, I. J.; Redmond, D.; Mangarin, L.; Pourpe, S.; Liu, C.; Zappasodi, R.; Zamarin, D.; Cavanaugh, J.; Castro, A. C.; Manfredi, M. G.; McGovern, K.; Merghoub, T.; Wolchok, J. D. |
| Article Title: | Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine |
| 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+ 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. © 2020, The Author(s). |
| Journal Title: | Nature Communications |
| Volume: | 11 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-08-11 |
| Start Page: | 4011 |
| Language: | English |
| DOI: | 10.1038/s41467-020-17750-z |
| PUBMED: | 32782249 |
| PROVIDER: | scopus |
| PMCID: | PMC7419300 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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