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

Luis Felipe Campesato, Sadna Budhu, Jeremy Tchaicha, Chien-Huan Weng, Mathieu Gigoux, Ivan Jose Cohen, David Redmond, Levi Mangarin, Stephane Pourpe, Cailian Liu, Roberta Zappasodi, Dmitriy Zamarin, Jill Cavanaugh, Alfredo C. Castro, Mark G. Manfredi, Karen McGovern, Taha Merghoub () and Jedd D. Wolchok ()
Additional contact information
Luis Felipe Campesato: Memorial Sloan Kettering Cancer Center
Sadna Budhu: Memorial Sloan Kettering Cancer Center
Jeremy Tchaicha: Ikena Oncology
Chien-Huan Weng: Memorial Sloan Kettering Cancer Center
Mathieu Gigoux: Memorial Sloan Kettering Cancer Center
Ivan Jose Cohen: Memorial Sloan Kettering Cancer Center
David Redmond: Memorial Sloan Kettering Cancer Center
Levi Mangarin: Memorial Sloan Kettering Cancer Center
Stephane Pourpe: Memorial Sloan Kettering Cancer Center
Cailian Liu: Memorial Sloan Kettering Cancer Center
Roberta Zappasodi: Memorial Sloan Kettering Cancer Center
Dmitriy Zamarin: Memorial Sloan Kettering Cancer Center
Jill Cavanaugh: Ikena Oncology
Alfredo C. Castro: Ikena Oncology
Mark G. Manfredi: Ikena Oncology
Karen McGovern: Ikena Oncology
Taha Merghoub: Memorial Sloan Kettering Cancer Center
Jedd D. Wolchok: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17750-z

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