Abstract
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 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.
Highlights
Immunotherapy has become a mainstay of cancer treatment and has reshaped the way we understand and approach certain cancer types[1,2]
We provide multiple lines of evidence to link methylthioadenosine phosphorylase (MTAP) loss, one of the most common genetic/epigenetic events in GBM, to changes in the tumor immune microenvironment
We demonstrate using patient data that MTAP deleted GBMs contain an immunosuppressive gene expression signature, with increased numbers of M2 macrophages and decreased lymphocyte activation
Summary
Immunotherapy has become a mainstay of cancer treatment and has reshaped the way we understand and approach certain cancer types[1,2]. GBM is the most common and lethal brain tumor, with a dismal median survival of 12–15 months from the time of d iagnosis[6] It is characterized by its profoundly immune-suppressive n ature[7,8]. Recent genomic studies have provided insight into the molecular mechanisms of GBM pathogenesis, revealing many commonly mutated genes in tumor c ells[11,12] Further studies, in both glioma and other types of cancer, have drawn association between genetic alterations and tumor evasion of immune surveillance, providing rationale for tailoring treatments to the cancer cells’ genetic composition[13–15]. We show that the MTA-induced alternative macrophage activation can be pharmacologically reversed
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