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

Blake, S. J., Stannard, K., Liu, J., Allen, S., Yong, M. C. R., Mittal, D., Aguilera, A. R., Miles, John, Lutzky, V. P., de Andrade, L. F., Martinet, L., Colonna, M., Takeda, K., Ku hnel, F., Gurlevik, E., Bernhardt, G., Teng, M. W. L. and Smyth, M. J. 2016. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discovery 6 (4) , pp. 446-459. 10.1158/2159-8290.CD-15-0944

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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 IFNγ, 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 IFNγ production and infiltration. Overall, these data demonstrate that blocking CD96 is a new and complementary immunotherapeutic strategy to reduce tumor metastases.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: American Association for Cancer Research
ISSN: 2159-8274
Date of Acceptance: 15 January 2016
Last Modified: 29 Jun 2017 09:17

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