Metastasis and immune evasion from extracellular cGAMP hydrolysis
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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 Dorsaint Julie-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 Toggle all authors (41)
Abstract
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.
Journal details
Journal Cancer Discovery
Volume 11
Issue number 5
Pages 1212-1227
Available online
Publication date
Full text links
Publisher website (DOI) 10.1158/2159-8290.CD-20-0387
Europe PubMed Central 33372007
Pubmed 33372007