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

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

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
Divisions of Gastroenterology, Hepatology and Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
3
Neuroimmunology Research Lab., Center for Excellence in Neuromics, Department of Neuroscience, Université de Montréal, Montréal, Québec, Canada.
4
Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada.
5
Dept of Environmental Health, Boston University School of Public Health, Boston, MA, USA.
6
Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina.
7
Center for Epidemiology, Biostatistics and Public Health (CEBES), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina.
8
Center for Neuro-Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA.
9
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
10
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.
11
The Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.

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.

PMID:
30962630
DOI:
10.1038/s41593-019-0370-y
[Indexed for MEDLINE]

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