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Glioblastoma (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 A 2B  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.

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization