CD96 Is an Immune Checkpoint That Regulates CD8þ T-cell Antitumor Function

Deepak Mittal, Ailin Lepletier, Jason Madore, Amelia Roman Aguilera, Kimberley Stannard, Stephen J. Blake, Vicki L.J. Whitehall, Cheng Liu, Mark L. Bettington, Kazuyoshi Takeda, Georgina V. Long, Richard A. Scolyer, Ruth Lan, Nathan Siemers, Alan Korman, Michele W.L. Teng, Robert J. Johnston, William C. Dougall, Mark J. Smyth

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75 Citations (Scopus)


CD96 is a novel target for cancer immunotherapy shown to infiltrating leukocytes both in mouse and human cancers regulate NK cell effector function and metastasis. Here, we using mRNA analysis, flow cytometry, and multiplex IHF. demonstrated that blocking CD96 suppressed primary tumor The combination of anti-CD96 with anti–PD-1 increased growth in a number of experimental mouse tumor models in a the percentage of IFNg-expressing CD8þ T lymphocytes. CD8þ T cell–dependent manner. DNAM-1/CD226, Batf3, Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted IL12p35, and IFNg were also critical, and CD96-deficient in superior antitumor responses, regardless of the ability of CD8þ T cells promoted greater tumor control than CD96-the anti-TIGIT isotype to engage FcR. The optimal triple sufficient CD8þ T cells. The antitumor activity of anti-CD96 combination was also dependent upon CD8þ T cells and therapy was independent of Fc-mediated effector function IFNg. Overall, these data demonstrate that CD96 is an and was more effective in dual combination with blockade immune checkpoint on CD8þ T cells and that blocking of a number of immune checkpoints, including PD-1, PD-L1, CD96 in combination with other immune-checkpoint inhi-TIGIT, and CTLA-4. We consistently observed coexpression bitors is a strategy to enhance T-cell activity and suppress of PD-1 with CD96 on CD8þ T lymphocytes in tumor-tumor growth.

Original languageEnglish
Pages (from-to)559-571
Number of pages13
JournalCancer Immunology Research
Issue number4
Publication statusPublished or Issued - Apr 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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