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

Maisa C. Takenaka, Galina Gabriely, Veit Rothhammer, Ivan D. Mascanfroni, Michael A. Wheeler, Chun Cheih Chao, Cristina Gutiérrez-Vázquez, Jessica Kenison, Emily C. Tjon, Andreia Barroso, Tyler Vandeventer, Kalil Alves de Lima, Sonja Rothweiler, Lior Mayo, Soufiene Ghannam, Stephanie Zandee, Luke Healy, David Sherr, Mauricio F. Farez, Alexandre PrattJack Antel, David A. Reardon, Hailei Zhang, Simon C. Robson, Gad Getz, Howard L. Weiner, Francisco J. Quintana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

318 Scopus citations

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.

Original languageEnglish
Pages (from-to)729-740
Number of pages12
JournalNature Neuroscience
Volume22
Issue number5
DOIs
StatePublished - 1 May 2019
Externally publishedYes

Funding

FundersFunder number
Dana Farber Cancer InstituteT32CA207201
Mallinkrodt PharmaceuticalsA219074, 1F32NS101790
National Institutes of HealthRSG-14-198-01-LIB
American Cancer Society
National Heart, Lung, and Blood InstituteR01HL057307
Fundación Alfonso Martín EscuderoCBB BDS-00503-16
Brain Science FoundationES07381
Deutsche ForschungsgemeinschaftRO4866 1/1
Fundação de Amparo à Pesquisa do Estado de Minas Gerais

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