Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39

Nat Neurosci. 2019 May;22(5):729-740. doi: 10.1038/s41593-019-0370-y. Epub 2019 Apr 8.

Abstract

Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-κB activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8+ T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Apyrase / metabolism*
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / metabolism
  • Cell Line, Tumor
  • Disease Progression
  • Glioblastoma / immunology*
  • Glioblastoma / metabolism
  • Humans
  • Kynurenine / metabolism*
  • Lipopolysaccharide Receptors / metabolism
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Tumor Microenvironment

Substances

  • Antigens, CD
  • Lipopolysaccharide Receptors
  • MIRN29 microRNA, mouse
  • MicroRNAs
  • Receptors, Aryl Hydrocarbon
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Kynurenine
  • Apyrase
  • CD39 antigen