dc.contributor.author | Mittal, Deepak | |
dc.contributor.author | Lepletier, Ailin | |
dc.contributor.author | Madore, Jason | |
dc.contributor.author | Aguilera, Amelia Roman | |
dc.contributor.author | Stannard, Kimberley | |
dc.contributor.author | Blake, Stephen J | |
dc.contributor.author | Whitehall, Vicki LJ | |
dc.contributor.author | Liu, Cheng | |
dc.contributor.author | Bettington, Mark L | |
dc.contributor.author | Takeda, Kazuyoshi | |
dc.contributor.author | Long, Georgina V | |
dc.contributor.author | Scolyer, Richard A | |
dc.contributor.author | Lan, Ruth | |
dc.contributor.author | Siemers, Nathan | |
dc.contributor.author | Korman, Alan | |
dc.contributor.author | Teng, Michele WL | |
dc.contributor.author | Johnston, Robert J | |
dc.contributor.author | Dougall, William C | |
dc.contributor.author | Smyth, Mark J | |
dc.date.accessioned | 2020-04-27T03:03:26Z | |
dc.date.available | 2020-04-27T03:03:26Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 2326-6066 | |
dc.identifier.doi | 10.1158/2326-6066.CIR-18-0637 | |
dc.identifier.uri | http://hdl.handle.net/10072/393407 | |
dc.description.abstract | CD96 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.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | American Association for Cancer Research (AACR) | |
dc.relation.ispartofpagefrom | 559 | |
dc.relation.ispartofpageto | 571 | |
dc.relation.ispartofissue | 4 | |
dc.relation.ispartofjournal | Cancer Immunology Research | |
dc.relation.ispartofvolume | 7 | |
dc.subject.fieldofresearch | Biological sciences | |
dc.subject.fieldofresearch | Clinical sciences | |
dc.subject.fieldofresearch | Immunology | |
dc.subject.fieldofresearch | Oncology and carcinogenesis | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences | |
dc.subject.fieldofresearchcode | 31 | |
dc.subject.fieldofresearchcode | 3202 | |
dc.subject.fieldofresearchcode | 3204 | |
dc.subject.fieldofresearchcode | 3211 | |
dc.subject.fieldofresearchcode | 3214 | |
dc.title | CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Mittal, 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.dateAccepted | 2019-01-15 | |
dc.date.updated | 2020-04-27T00:29:57Z | |
dc.description.version | Accepted 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.hasfulltext | Full Text | |
gro.griffith.author | Lepletier De Oliveira, Ailin | |