Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy

Stephen J. Blake, Kimberley Stannard, Jing Liu, Stacey Allen, Michelle C.R. Yong, Deepak Mittal, Amelia Roman Aguilera, John J. Miles, Viviana P. Lutzky, Lucas Ferrari de Andrade, Ludovic Martinet, Marco Colonna, Kazuyoshi Takeda, Florian Kühnel, Engin Gurlevik, Günter Bernhardt, Michele W.L. Teng, Mark J. Smyth

Research output: Contribution to journalArticlepeer-review

182 Scopus citations


CD96 has recently been shown as a negative regulator of mouse natural killer (NK)–cell activity, with Cd96-/- mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFN?, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti–CTLA-4, anti–PD-1, or doxorubicin chemotherapy. Blocking CD96 in Tigit-/- mice significantly reduced experimental and spontaneous metastases compared with its activity in wild-type mice. Co-blockade of CD96 and PD-1 potently inhibited lung metastases, with the combination increasing local NK-cell IFN? production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases. Significance: This article illustrates the antimetastatic activity and mechanism of action of an anti-CD96 antibody that inhibits the CD96–CD155 interaction and stimulates NK-cell function. Targeting host CD96 is shown to complement surgery and conventional immune checkpoint blockade.

Original languageEnglish
Pages (from-to)446-459
Number of pages14
JournalCancer discovery
Issue number4
StatePublished - Apr 2016


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