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| Item Type: | Article |
|---|---|
| Title: | A protective cGAMP-mediated anti-tumor immune response can proceed without LRRC8/VRAC channels |
| Creators Name: | Thöne, Fabian M.B., Polovitskaya, Maya M., Höpken, Uta E., Rehm, Armin and Jentsch, Thomas J. |
| Abstract: | 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. |
| Keywords: | Cancer Biology, Cyclic Nucleotide, Tumor Immunology, Innate Immunity, Chloride Channel, VSOR, SWELL1, Adaptive Immune Response, Cytokines, Cell Proliferation |
| Source: | Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Publisher: | Elsevier / American Society for Biochemistry and Molecular Biology |
| Page Range: | 111060 |
| Date: | 17 December 2025 |
| Official Publication: | https://doi.org/10.1016/j.jbc.2025.111060 |
| PubMed: | View item in PubMed |
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