Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine. Academic Article uri icon



  • 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.

publication date

  • August 11, 2020



  • Kynurenine
  • Macrophages
  • Receptors, Aryl Hydrocarbon
  • T-Lymphocytes, Regulatory


PubMed Central ID

  • PMC7419300

Scopus Document Identifier

  • 85089360125

Digital Object Identifier (DOI)

  • 10.1038/s41467-020-17750-z

PubMed ID

  • 32782249

Additional Document Info


  • 11


  • 1