2. Academic Validation
  3. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine

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

  • Nat Commun. 2020 Aug 11;11(1):4011. doi: 10.1038/s41467-020-17750-z.
Luis Felipe Campesato 1 2,  Sadna Budhu 1 2,  Jeremy Tchaicha 3,  Chien-Huan Weng 1 2,  Mathieu Gigoux 1 2,  Ivan Jose Cohen 4,  David Redmond 1 2,  Levi Mangarin 1 2,  Stephane Pourpe 1 2,  Cailian Liu 1 2,  Roberta Zappasodi 1 2,  Dmitriy Zamarin 1 2,  Jill Cavanaugh 3,  Alfredo C Castro 3,  Mark G Manfredi 3,  Karen McGovern 3,  Taha Merghoub # 5 6,  Jedd D Wolchok # 7 8
Affiliations

Affiliations

  • 1 Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Ikena Oncology, Boston, MA, USA.
  • 4 Department of Neurology and Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 5 Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org.
  • 6 Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. merghout@mskcc.org.
  • 7 Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org.
  • 8 Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. wolchokj@mskcc.org.
  • # Contributed equally.
PMID: 32782249 DOI: 10.1038/s41467-020-17750-z
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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