Metastasis and immune evasion from extracellular cGAMP hydrolysis

Jun Li, Mercedes A Duran, Ninjit Dhanota, Walid K Chatila, Sarah E Bettigole, John Kwon, Roshan K Sriram, Matthew Philip Humphries, Manuel Salto-Tellez, Jacqueline A James, Matthew G Hanna, Johannes C Melms, Sreeram Vallabhaneni, Kevin Litchfield, Ieva Usaite, Dhruva Biswas, Rohan Bareja, Hao Wei Li, Maria Laura Martin, Princesca DorsaintJulie-Ann Cavallo, Peng Li, Chantal Pauli, Lee Gottesdiener, Benjamin J DiPardo, Travis J Hollmann, Taha Merghoub, Hannah Y Wen, Jorge S Reis-Filho, Nadeem Riaz, Shin-San Michael Su, Anusha Kalbasi, Neil Vasan, Simon N Powell, Jedd D Wolchok, Olivier Elemento, Charles Swanton, Alexander N Shoushtari, Eileen E Parkes, Benjamin Izar, Samuel F Bakhoum

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Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway.

Original languageEnglish
Pages (from-to)xx
JournalCancer discovery
VolumeEarly Online
Early online date28 Dec 2020
Publication statusEarly online date - 28 Dec 2020


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