| 論文作者 |
Cao, LM; Wang, L; Li, ZH; Wei, X; Ding, JQ; Zhou, C; Chen, X; Huang, ZC; Shao, ZG; Shen, JC; Lou, HF; Zhao, KQ; Huang, YW; Yang, YQ; Liu, H; Sun, YM; Niu, JL; Jiang, S; Lu, R; Tang, LH; Zhang, XM; Zhang, HB; Xiao, YC; Chen, JF; Ma, SX; Gao, CJ; Meng, GX; Liu, L; Qiu, ZZ; Wang, HP; Deng, LF; Ye, YQ; Jia, XM; Li, HB; Xiao, H |
| 摘要 |
The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat-containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions. TCR signaling acts as a physiological signal to open the VRAC pore through phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and reactive oxygen species (ROS). This allows the rapid uptake of cGAMP and STING activation in mouse and human T cells and induction of interferon-alpha/beta, which up-regulate granzymes and IFN-gamma in CD8 T cells. Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies. |
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