放疗通过LRRC8A/C容积调节性阴离子通道传递环鸟苷酸-腺苷酸（cGAMP）增强抗癌CD8 T细胞反应。

Radiotherapy enhances anticancer CD8 T cell responses by cGAMP transfer through LRRC8A/C volume-regulated anion channels.

作者信息

Cao Limin, Wang Li, Li Zhihong, Wei Xia, Ding Jinqiu, Zhou Chun, Chen Xia, Huang Zhicheng, Shao Zhugui, Shen Junchen, Lou Hongfei, Zhao Keqing, Huang Yuwei, Yang Yuanqin, Liu Han, Sun Yumeng, Niu Junling, Jiang Shan, Lu Rong, Tang Longhai, Zhang Xiaoming, Zhang Haibing, Xiao Yichuan, Chen Jianfeng, Ma Shixin, Gao Chengjiang, Meng Guangxun, Liu Li, Qiu Zhaozhu, Wang Haopeng, Deng Liufu, Ye Youqiong, Jia Xin-Ming, Li Huabin, Xiao Hui

机构信息

State Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200092, China.

出版信息

Sci Immunol. 2025 Jun 27;10(108):eadn1630. doi: 10.1126/sciimmunol.adn1630.

DOI:10.1126/sciimmunol.adn1630

PMID:40577443

Abstract

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)P] 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-α/β, which up-regulate granzymes and IFN-γ 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.

摘要

容积调节性阴离子通道（VRACs）可跨细胞膜转运渗透压溶质、神经递质和环状GMP-AMP（cGAMP），从而调节细胞容积和宿主防御。我们报告富含亮氨酸重复序列8A/C（LRRC8A/C）的VRAC在癌症放疗和化疗的免疫反应中起关键作用。VRACs将cGAMP从受照射的癌细胞转移至浸润的CD4和CD8 T细胞，从而增强其效应功能。TCR信号作为一种生理信号，通过磷脂酰肌醇4,5-二磷酸[PI(4,5)P]和活性氧（ROS）打开VRAC孔道。这使得小鼠和人类T细胞能够快速摄取cGAMP并激活STING，进而诱导干扰素-α/β，上调CD8 T细胞中的颗粒酶和IFN-γ。抑制细胞外水解酶CD39和ENPP1可维持细胞外ATP和cGAMP，促进VRAC增强的CD8 T细胞抗癌功能。因此，VRACs将cGAMP转移至T细胞可能是一种未来癌症治疗中可靶向的策略。