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

Blake, Stephen J., Stannard, Kimberley, Liu, Jing, Allen, Stacey, Yong, Michelle C.R., Mittal, Deepak, Aguilera, Amelia Roman, Miles, John J., Lutzky, Viviana P., Ferrari de Andrade, Lucas, Martinet, Ludovic, Colonna, Marco, Takeda, Kazuyoshi, Kühnel, Florian, Gurlevik, Engin, Bernhardt, Günter, Teng, Michele W.L., and Smyth, Mark J. (2016) Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer Discovery, 6 (4). pp. 446-459.

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Abstract

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.

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.

Item ID: 44959
Item Type: Article (Research - C1)
ISSN: 2159-8274
Funders: National Health and Medical Research Council (NHMRC), Cancer Council of Queensland (CCQ), Cancer Research Institute (CRI), Prostate Cancer Foundation of Australia (PCFA), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Projects and Grants: NHMRC Project Grant 1044392, NHMRC Development Grant 1093566, CCQ Project Grant 1083776, CRI CLIP Grant, Senior Principal Research Fellowship 1078671, NHMRC Career Development Fellowship, PCFA Grant, CNPq PhD Fellowship
Date Deposited: 04 May 2017 02:53
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1112 Oncology and Carcinogenesis > 111201 Cancer Cell Biology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 100%
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