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dc.contributor.authorLi, J
dc.contributor.authorDuran, MA
dc.contributor.authorDhanota, N
dc.contributor.authorChatila, WK
dc.contributor.authorBettigole, SE
dc.contributor.authorKwon, J
dc.contributor.authorSriram, RK
dc.contributor.authorHumphries, MP
dc.contributor.authorSalto-Tellez, M
dc.contributor.authorJames, JA
dc.contributor.authorHanna, MG
dc.contributor.authorMelms, JC
dc.contributor.authorVallabhaneni, S
dc.contributor.authorLitchfield, K
dc.contributor.authorUsaite, I
dc.contributor.authorBiswas, D
dc.contributor.authorBareja, R
dc.contributor.authorLi, HW
dc.contributor.authorMartin, ML
dc.contributor.authorDorsaint, P
dc.contributor.authorCavallo, J-A
dc.contributor.authorLi, P
dc.contributor.authorPauli, C
dc.contributor.authorGottesdiener, L
dc.contributor.authorDiPardo, BJ
dc.contributor.authorHollmann, TJ
dc.contributor.authorMerghoub, T
dc.contributor.authorWen, HY
dc.contributor.authorReis-Filho, JS
dc.contributor.authorRiaz, N
dc.contributor.authorSu, S-SM
dc.contributor.authorKalbasi, A
dc.contributor.authorVasan, N
dc.contributor.authorPowell, SN
dc.contributor.authorWolchok, JD
dc.contributor.authorElemento, O
dc.contributor.authorSwanton, C
dc.contributor.authorShoushtari, AN
dc.contributor.authorParkes, EE
dc.contributor.authorIzar, B
dc.contributor.authorBakhoum, SF
dc.date.accessioned2021-03-04T16:20:42Z
dc.date.available2021-03-04T16:20:42Z
dc.date.issued2021-05-01
dc.identifier.citationCancer discovery, 2020
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4398
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-20-0387
dc.description.abstractCytosolic 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 wild-type 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-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.This article is highlighted in the In This Issue feature, p. 995.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleMetastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.
dc.typeJournal Article
dcterms.dateAccepted2020-12-11
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/2159-8290.cd-20-0387
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-12-28
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Integrated Pathology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Integrated Pathology
pubs.publication-statusPublished
pubs.embargo.termsNot known
icr.researchteamIntegrated Pathology
icr.researchteamIntegrated Pathology
dc.contributor.icrauthorSalto-Tellez, Manuel


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