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Cancer Discov. 2016 Apr;6(4):446-59. doi: 10.1158/2159-8290.CD-15-0944. Epub 2016 Jan 19.

Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

Author information

1
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
2
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
3
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
4
Human Immunity, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom.
5
Human Immunity, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
7
Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
8
Department for Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.
9
Institute of Immunology, Hannover Medical School, Hannover, Germany.
10
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, The University of Queensland, Herston, Queensland, Australia.
11
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, The University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.

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.

PMID:
26787820
DOI:
10.1158/2159-8290.CD-15-0944
[Indexed for MEDLINE]
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