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dc.contributor.authorMittal, Deepak
dc.contributor.authorLepletier, Ailin
dc.contributor.authorMadore, Jason
dc.contributor.authorAguilera, Amelia Roman
dc.contributor.authorStannard, Kimberley
dc.contributor.authorBlake, Stephen J
dc.contributor.authorWhitehall, Vicki LJ
dc.contributor.authorLiu, Cheng
dc.contributor.authorBettington, Mark L
dc.contributor.authorTakeda, Kazuyoshi
dc.contributor.authorLong, Georgina V
dc.contributor.authorScolyer, Richard A
dc.contributor.authorLan, Ruth
dc.contributor.authorSiemers, Nathan
dc.contributor.authorKorman, Alan
dc.contributor.authorTeng, Michele WL
dc.contributor.authorJohnston, Robert J
dc.contributor.authorDougall, William C
dc.contributor.authorSmyth, Mark J
dc.date.accessioned2020-04-27T03:03:26Z
dc.date.available2020-04-27T03:03:26Z
dc.date.issued2019
dc.identifier.issn2326-6066
dc.identifier.doi10.1158/2326-6066.CIR-18-0637
dc.identifier.urihttp://hdl.handle.net/10072/393407
dc.description.abstractCD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8+ T cell–dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNγ were also critical, and CD96-deficient CD8+ T cells promoted greater tumor control than CD96-sufficient CD8+ T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8+ T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti–PD-1 increased the percentage of IFNγ-expressing CD8+ T lymphocytes. Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8+ T cells and IFNγ. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8+ T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.relation.ispartofpagefrom559
dc.relation.ispartofpageto571
dc.relation.ispartofissue4
dc.relation.ispartofjournalCancer Immunology Research
dc.relation.ispartofvolume7
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchImmunology
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode3202
dc.subject.fieldofresearchcode3204
dc.subject.fieldofresearchcode3211
dc.subject.fieldofresearchcode3214
dc.titleCD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationMittal, D; Lepletier, A; Madore, J; Aguilera, AR; Stannard, K; Blake, SJ; Whitehall, VLJ; Liu, C; Bettington, ML; Takeda, K; Long, GV; Scolyer, RA; Lan, R; Siemers, N; Korman, A; Teng, MWL; Johnston, RJ; Dougall, WC; Smyth, MJ, CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function, Cancer Immunology Research, 2019, 7 (4), pp. 559-571
dcterms.dateAccepted2019-01-15
dc.date.updated2020-04-27T00:29:57Z
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2019 AACR. This is the author-manuscript version of the paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal link for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorLepletier De Oliveira, Ailin


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