LRRC8/VRACチャネルを必要としない保護的なcGAMP媒介抗腫瘍免疫応答が可能

The volume-regulated anion channel VRAC is a hetero-hexamer composed of LRRC8A and any of the four other LRRC8 paralogs (LRRC8B-E). Depending on their subunit composition, VRACs not only transport chloride, but also a range of organic substrates including 2'3'-cGAMP (cGAMP). Transfer of this immunomodulator from tumor to host cells is critical for anti-tumor immunity. Whether this process depends on VRAC in vivo remains incompletely understood. To address this issue, we studied subcutaneous MC38 and B16-F10 tumors in syngeneic mice. Enhanced growth of MC38 tumors lacking cGAMP production confirmed the importance of tumor-produced cGAMP. The impact of VRAC-mediated cGAMP-efflux from tumor cells and its uptake into cells of the tumor microenvironment was investigated using LRRC8A-deficient tumor cells and recipient mice with selective LRRC8 subunit disruptions, respectively. Changed serum cytokines indicated moderate immunomodulatory effects of VRAC-mediated cGAMP export from MC38 tumors. However, tumor growth and the cGAMP-mediated anti-tumor immune response were independent of both, tumor- and host-expressed VRAC. Disruption of any of the non-essential subunits, LRRC8B-LRRC8E, had no discernible effect on T or B cell development in mice. Whereas tumor-produced cGAMP markedly suppresses tumor growth, transport of this immunomodulator to the tumor environment primarily involves transporters distinct from VRAC.