Metastasis and immune evasion from extracellular cGAMP hydrolysis.
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Publication Date
2020-12-28ICR Author
Author
Li, J
Duran, MA
Dhanota, N
Chatila, WK
Bettigole, SE
Kwon, J
Sriram, RK
Humphries, MP
Salto-Tellez, M
James, JA
Hanna, MG
Melms, JC
Vallabhaneni, S
Litchfield, K
Usaite, I
Biswas, D
Bareja, R
Li, HW
Martin, ML
Dorsaint, P
Cavallo, J-A
Li, P
Pauli, C
Gottesdiener, L
DiPardo, BJ
Hollmann, TJ
Merghoub, T
Wen, HY
Reis-Filho, JS
Riaz, N
Su, S-SM
Kalbasi, A
Vasan, N
Powell, SN
Wolchok, JD
Elemento, O
Swanton, C
Shoushtari, AN
Parkes, EE
Izar, B
Bakhoum, SF
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Licenseref URL
http://creativecommons.org/licenses/by/4.0/Version
AM
Version of record
Research team
Integrated Pathology
Language
eng
Date accepted
2020-12-11
License start date
2020-12-28
Citation
Cancer discovery, 2020