CD96 has recently been shown as a negative regulator of mouse NK cell activity, with Cd96-/- mice displaying hyper-responsive 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 anti-metastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1) and IFN-γ, but independent of activating Fc receptors. Anti-CD96 was more effective in combination with anti-CTLA4, anti-PD1 or doxorubicin chemotherapy. Blocking CD96 in Tigit-/- mice significantly reduced experimental and spontaneous metastases compared to its activity in WT mice. Co-blockade of CD96 and PD1 potently inhibited lung metastases, with the combination increasing local NK cell IFN-γ production and infiltration. Overall these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases.
- Received August 4, 2015.
- Revision received January 12, 2016.
- Accepted January 15, 2016.
- Copyright © 2016, American Association for Cancer Research.