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
  • 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. [email protected].
  • 6. Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • 7. Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • 8. Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • # 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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