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Extracellular 2’3’-cGAMP is an immunotransmitter produced by cancer cells and regulated by ENPP1

By Jacqueline A Carozza, Volker Böhnert, Khanh C Nguyen, Gemini Skariah, Kelsey E Shaw, Jenifer A Brown, Marjan Rafat, Rie von Eyben, Edward E Graves, Jeffrey S Glenn, Mark Smith, Lingyin Li

Posted 03 Feb 2019
bioRxiv DOI: 10.1101/539312

2’3’-cyclic GMP-AMP (cGAMP) is characterized as an intracellular second messenger that is synthesized in response to cytosolic dsDNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here, using mass spectrometry, we detected that cGAMP is continuously exported as a soluble factor by an engineered cell line but then efficiently cleared by ENPP1, explaining why it has escaped detection until now. By developing potent, specific, and cell impermeable ENPP1 inhibitors, we detected that cancer cells continuously export cGAMP in culture at steady state and at higher levels when treated with ionizing radiation (IR). In tumors, depletion of extracellular cGAMP using a neutralizing protein decreased tumor-associated immune cell infiltration in a tumor cGAS and host STING dependent manner. Depletion of extracellular cGAMP also abolished the curative effect of IR. Boosting extracellular cGAMP by ENPP1 inhibitors synergizes with IR to shrink tumors in mice. In conclusion, extracellular cGAMP is an anti-cancer immunotransmitter that could be stimulated and harnessed to treat less immunogenic cancers.

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