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 IFN? 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 IFN?-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 IFN?. 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.

Authors	Mittal, Deepak; Lepletier, Ailin; Madore, Jason; Aguilera, Amelia Roman; Stannard, Kimberley; Blake, Stephen J; Whitehall, Vicki L J; Liu, Cheng; Bettington, Mark L; Takeda, Kazuyoshi; Long, Georgina V; Scolyer, Richard A; Lan, Ruth; Siemers, Nathan; Korman, Alan; Teng, Michele W L; Johnston, Robert J; Dougall, William C; Smyth, Mark J
Journal	Cancer Immunology Research
Pages	559-571
Volume	7
Date	1/03/2019
Grant ID	6980
Funding Body	Cancer Research Institute
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/2326-6066.CIR-18-0637