Apr 16, 2020

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

BioRxiv : the Preprint Server for Biology
Anthony F CordovaLi


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, which we recently described as an immunotransmitter exported by cancer cells and imported into local responder cells of unknown identities to promote anti-tumoral immunity, with irradiation enhancing this effect. Here, in low-dose irradiated murine tumors, we identified CD4+ T cells, M1 macrophages, and NKG2DLow NK cells as cGAMP responder cells that have decreased STING activation upon depletion of extracellular cGAMP. At higher doses of radiation, extracellular cGAMP promoted the death of T cells and macrophages. Furthermore, we identified the orphan protein SLC46A2 as the dominant importer of cGAMP and select bacterial CDNs in human macrophages and monocytes. 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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