Journal Article
. 2020 Aug; 11(1):4011.
doi: 10.1038/s41467-020-17750-z.

Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

Luis Felipe Campesato 1 Sadna Budhu 1 Jeremy Tchaicha 2 Chien-Huan Weng 1 Mathieu Gigoux 1 Ivan Jose Cohen 3 David Redmond 1 Levi Mangarin 1 Stephane Pourpe 1 Cailian Liu 1 Roberta Zappasodi 1 Dmitriy Zamarin 1 Jill Cavanaugh 2 Alfredo C Castro 2 Mark G Manfredi 2 Karen McGovern 2 Taha Merghoub 4 Jedd D Wolchok 5 
Affiliations
  • PMID: 32782249
  •     53 References
  •     41 citations

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.

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