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dc.contributor.authorLi, Xian-Yang
dc.contributor.authorMoesta, Achim K
dc.contributor.authorXiao, Christos
dc.contributor.authorNakamura, Kyohei
dc.contributor.authorCasey, Mika
dc.contributor.authorZhang, Haiyan
dc.contributor.authorMadore, Jason
dc.contributor.authorLepletier, Ailin
dc.contributor.authorAguilera, Amelia Roman
dc.contributor.authorSundarrajan, Ashmitha
dc.contributor.authorJacoberger-Foissac, Celia
dc.contributor.authorWong, Clifford
dc.contributor.authordela Cruz, Tracy
dc.contributor.authorWelch, Megan
dc.contributor.authorLerner, Alana G
dc.contributor.authorSpatola, Bradley N
dc.contributor.authorSoros, Vanessa B
dc.contributor.authorCorbin, John
dc.contributor.authorAnderson, Ana C
dc.contributor.authorEffern, Maike
dc.contributor.authorHoelzel, Michael
dc.contributor.authorRobson, Simon C
dc.contributor.authorJohnston, Rebecca L
dc.contributor.authorWaddell, Nicola
dc.contributor.authorSmith, Corey
dc.contributor.authorBald, Tobias
dc.contributor.authorGeetha, Nishamol
dc.contributor.authorBeers, Courtney
dc.contributor.authorTeng, Michele WL
dc.contributor.authorSmyth, Mark J
dc.date.accessioned2020-04-27T22:18:23Z
dc.date.available2020-04-27T22:18:23Z
dc.date.issued2019
dc.identifier.issn2159-8274
dc.identifier.doi10.1158/2159-8290.CD-19-0541
dc.identifier.urihttp://hdl.handle.net/10072/393431
dc.description.abstractWe explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP–P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP–P2X7–ASC–NALP3-inflammasome–IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell–poor tumors and rescued anti–PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein–Barr virus–specific T-cell transfer. Significance: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP–P2X7–inflammasome–IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti–PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.relation.ispartofpagefrom1754
dc.relation.ispartofpageto1773
dc.relation.ispartofissue12
dc.relation.ispartofjournalCancer Discovery
dc.relation.ispartofvolume9
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchcode3211
dc.titleTargeting CD39 in cancer reveals an extracellular ATP-and inflammasome-driven tumor immunity
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationLi, XY; Moesta, AK; Xiao, C; Nakamura, K; Casey, M; Zhang, H; Madore, J; Lepletier, A; Aguilera, AR; Sundarrajan, A; Jacoberger-Foissac, C; Wong, C; de la Cruz, T; Welch, M; Lerner, AG; Spatola, BN; Soros, VB; Corbin, J; Anderson, AC; Effern, M; Hölzel, M; Robson, SC; Johnston, RL; Waddell, N; Smith, C; Bald, T; Geetha, N; Beers, C; Teng, MWL; Smyth, MJ, Targeting CD39 in cancer reveals an extracellular ATP-and inflammasome-driven tumor immunity, Cancer Discovery, 2019, 9 (12), pp. 1754-1773
dcterms.dateAccepted2019-10-01
dc.date.updated2020-04-27T00:46:13Z
gro.hasfulltextNo Full Text
gro.griffith.authorLepletier De Oliveira, Ailin


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