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bioRxiv · 10.1101/2020.04.15.043299

Murine M1 macrophages are among the direct responders to tumor-derived extracellular cGAMP and their human counterparts use SLC46A2 to import cGAMP

Cordova, A. F.·Ritchie, C.·Böhnert, V.·Mardjuki, R. E.·Li, L.
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Abstract

Administration of exogenous CDNs to activate the cGAMP-STING pathway is a promising therapeutic strategy to unleash the full potential of cancer immunotherapy. This strategy mirrors the role of endogenous extracellular cGAMP, an immunotransmitter that is transferred from cancer cells to cGAMP-sensing cells in the host, promoting immunity. However, the CDN import mechanisms used by host cells within tumors remain unknown. Here we identified the protein SLC46A2 as the dominant cGAMP importer in primary human monocytes. Furthermore, we discovered that monocytes and M1-polarized macrophages directly sense tumor-derived extracellular cGAMP in murine tumors. Finally, we demonstrated that SLC46A2 is the dominant cGAMP importer in monocyte-derived macrophages. Together, we provide the first cellular and molecular mechanisms of cGAMP as an immunotransmitter, paving the way for effective STING pathway therapeutics.

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Cordova, A. F., Ritchie, C., Böhnert, V., Mardjuki, R. E., Li, L.. 2020-04-16. Murine M1 macrophages are among the direct responders to tumor-derived extracellular cGAMP and their human counterparts use SLC46A2 to import cGAMP. https://doi.org/10.1101/2020.04.15.043299

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