Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity.
Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity.
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DOI：
10.1038/s43018-020-0028-4
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发表时间：
2020-02
期刊：
影响因子：
22.7
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Carozza JA;Böhnert V;Nguyen KC;Skariah G;Shaw KE;Brown JA;Rafat M;von Eyben R;Graves EE;Glenn JS;Smith M;Li L
2 '3'-环GMP-AMP（cGAMP）是细胞内第二信使，其响应于胞质双链DNA而合成并激活先天免疫STING途径。我们先前发现的其胞外水解酶ENPP 1暗示了胞外cGAMP的存在。在这里，我们检测到cGAMP被连续输出，但随后被ENPP 1有效清除，这解释了为什么它以前没有被检测到。通过开发有效的，特异性的和细胞不可渗透的ENPP 1抑制剂，我们发现癌细胞在用电离辐射（IR）处理时以稳定状态和更高水平持续输出cGAMP。在小鼠肿瘤中，细胞外cGAMP的耗竭降低了肿瘤相关的免疫细胞浸润并消除了IR的疗效。用ENPP 1抑制剂增强细胞外cGAMP与IR协同作用以延迟肿瘤生长。总之，细胞外cGAMP是一种抗癌免疫递质，可用于治疗具有低免疫原性的癌症。
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 anti-cancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Jønsson KL;Laustsen A;Krapp C;Skipper KA;Thavachelvam K;Hotter D;Egedal JH;Kjolby M;Mohammadi P;Prabakaran T;Sørensen LK;Sun C;Jensen SB;Holm CK;Lebbink RJ;Johannsen M;Nyegaard M;Mikkelsen JG;Kirchhoff F;Paludan SR;Jakobsen MR
通讯作者：
Jakobsen MR