文章目录

细胞外cGAMP是一种癌细胞产生的免疫递质，参与辐射诱导的抗癌免疫

原文发布日期：2020-02-24

英文摘要：

摘要翻译：

原文链接：

文章：

细胞外cGAMP是一种癌细胞产生的免疫递质，参与辐射诱导的抗癌免疫

Extracellular cGAMP is a cancer-cell-produced immunotransmitter involved in radiation-induced anticancer immunity

原文发布日期：2020-02-24

英文摘要：

2′3′-Cyclic GMP-AMP (cGAMP) is an intracellular second messenger that is synthesized in response to cytosolic double-stranded DNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here we detected that cGAMP is continuously exported but then efficiently cleared by ENPP1, explaining why it has previously escaped detection. By developing potent, specific and cell-impermeable ENPP1 inhibitors, we found that cancer cells continuously export cGAMP in culture at steady state and at higher levels when treated with ionizing radiation (IR). In mouse tumors, depletion of extracellular cGAMP decreased tumor-associated immune cell infiltration and abolished the curative effect of IR. Boosting extracellular cGAMP with ENPP1 inhibitors synergized with IR to delay tumor growth. In conclusion, extracellular cGAMP is an anticancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.

摘要翻译：

2′3′-胞内第二信使胞外双链DNA激活 innate免疫STING途径。我们之前发现其外泌水解酶ENPP1提示了外泌cGAMP的存在性。在此处我们检测到其持续转运但被ENPP1高效清除，解释了为何此物质一直未被发现。通过开发强效、特异的且细胞不可穿透的ENPP1抑制剂，我们发现癌细胞在培养基中处于平衡状态下持续外泌cGAMP，并且在受到辐射处理时水平更高。在小鼠肿瘤模型中，外泌cGAMP缺乏减少了肿瘤相关免疫细胞的浸润并终止了离子izing辐射的治愈效果。使用ENPP1抑制剂增强外泌cGAMP协同作用于辐射可延缓肿瘤生长。结论：外泌cGAMP是一种抗癌免疫传输因子，可被用于治疗低免疫性的癌症。