A protective cGAMP-mediated anti-tumor immune response can proceed without LRRC8/VRAC channels

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 antitumor 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 antitumor 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. While tumor-produced cGAMP markedly suppresses tumor growth, transport of this immunomodulator to the tumor environment primarily involves transporters distinct from VRAC.