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

Landon Hansen, Rui Yang, Karolina I Woroniecka, Lee Chen, Hai Yan, Yiping He
doi: https://doi.org/10.1101/329664
Landon Hansen
Duke University School of Medicine
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Rui Yang
Duke University School of Medicine
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Karolina I Woroniecka
Duke University School of Medicine
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Lee Chen
Duke University School of Medicine
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Hai Yan
Duke University School of Medicine
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Yiping He
Duke University School of Medicine
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  • For correspondence: yiping.he@duke.edu
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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 A2B 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 MTAP-null GBM.

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Posted May 24, 2018.
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MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization
Landon Hansen, Rui Yang, Karolina I Woroniecka, Lee Chen, Hai Yan, Yiping He
bioRxiv 329664; doi: https://doi.org/10.1101/329664
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MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization
Landon Hansen, Rui Yang, Karolina I Woroniecka, Lee Chen, Hai Yan, Yiping He
bioRxiv 329664; doi: https://doi.org/10.1101/329664

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