Author:
Hansen Landon J.,Yang Rui,Roso Kristen,Wang Wenzhe,Chen Lee,Yang Qing,Pirozzi Christopher J.,He Yiping
Abstract
AbstractGlioblastoma (GBM) is a lethal brain cancer known for its potent immunosuppressive effects. Loss of Methylthioadenosine Phosphorylase (MTAP) expression, via gene deletion or epigenetic silencing, is one of the most common alterations in GBM. Here we show that MTAP loss in GBM cells is correlated with differential expression of immune regulatory genes. In silico analysis of gene expression profiles in GBM samples revealed that low MTAP expression is correlated with an increased proportion of M2 macrophages. Using in vitro macrophage models, we found that methylthioadenosine (MTA), the metabolite that accumulates as a result of MTAP loss in GBM cells, promotes the immunosuppressive alternative activation (M2) of macrophages. We show that this effect of MTA on macrophages is independent of IL4/IL3 signaling, is mediated by the adenosine A2B receptor, and can be pharmacologically reversed. This study suggests that MTAP loss in GBM cells may contribute to the immunosuppressive tumor microenvironment, and that MTAP status should be considered for characterizing GBM immune states and devising immunotherapy-based approaches for treating MTAP-null GBM.
Funder
National Institutes of Health
National Comprehensive Cancer Center Network Young Investigator Award
National Institute of Neurological Disorders and Stroke
Duke SPORE in Brain Cancer
Southeastern Brain Tumor Foundation
Circle of Service Foundation
Publisher
Springer Science and Business Media LLC
Cited by
8 articles.
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