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

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 reduced proportions of γδT cells, fewer activated CD4 cells, and 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 contributes to the immunosuppressive microenvironment, and that MTAP status should be a factor for consideration in understanding GBM immune states and devising immunotherapy-based approaches for treating MTAPnull GBM. laboratory for the LC-MS/MS metabolite analysis, and Heather Hemric, Laura-Leigh Rowlette, and Holly Dressman of the Duke Sequencing and Genomic Technologies Shared Resource for the Affymetrix array processing service.

9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy

“…Published reports indicate that tumor-derived MTA metabolite acts to suppress T-cell functions 62 and to inhibit arginine methylation of STAT1, thus leading to diminution of the biological responses to interferons (IFNs) 63 , which is essential for T-cell function and PD-L1 expression. Other than impaired T-cell function and interferon signaling, MTAP loss has been shown to promote the immunosuppressive alternative activation of M2-like macrophages in GBM cell lines 64 . In addition, CDKN2A deletion leads to constitutive CDK4/6 activity, which is although best known for its function in promoting cell cycle progression, emerging evidence indicates its roles in regulating T-cell biology 65 .…”