Oncotarget

Research Papers:

A novel immunotherapy targeting MMP-14 limits hypoxia, immune suppression and metastasis in triple-negative breast cancer models

Binbing Ling, Kathleen Watt, Sunandan Banerjee, Daniel Newsted, Peter Truesdell, Jarrett Adams, Sachdev S. Sidhu and Andrew WB Craig _

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Oncotarget. 2017; 8:58372-58385. https://doi.org/10.18632/oncotarget.17702

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Abstract

Binbing Ling1, Kathleen Watt1, Sunandan Banerjee2, Daniel Newsted1, Peter Truesdell1, Jarrett Adams2, Sachdev S. Sidhu2 and Andrew W.B. Craig1

1Department of Biomedical and Molecular Sciences, Queen’s University, Cancer Biology and Genetics Division, Queen’s Cancer Research Institute, Kingston, ON, Canada

2The Donnelly Centre, University of Toronto, Toronto, ON, Canada

Correspondence to:

Andrew W.B. Craig, email: andrew.craig@queensu.ca

Keywords: MMP-14, inhibitory antibody, breast cancer, hypoxia, metastasis

Received: November 04, 2016     Accepted: April 22, 2017     Published: May 09, 2017

ABSTRACT

Matrix metalloproteinase-14 (MMP-14) is a clinically relevant target in metastatic cancers due to its role in tumor progression and metastasis. Since active MMP-14 is localized on the cell surface, it is amenable to antibody-mediated blockade in cancer, and here we describe our efforts to develop novel inhibitory anti-MMP-14 antibodies. A phage-displayed synthetic humanized Fab library was screened against the extracellular domain of MMP-14 and a panel of MMP14-specific Fabs were identified. A lead antibody that inhibits the catalytic domain of MMP-14 (Fab 3369) was identified and treatment of MDA-MB-231 breast cancer cells with Fab 3369 led to significant loss of extracellular matrix degradation and cell invasion abilities. In mammary orthotopic tumor xenograft assays, MMP-14 blockade by IgG 3369 limited tumor growth and metastasis. Analysis of tumor tissue sections revealed that MMP-14 blockade limited tumor neoangiogenesis and hypoxia. Similar effects of MMP-14 blockade in syngeneic 4T1 mammary tumors were observed, along with increased detection of cytotoxic immune cell markers. In conclusion, we show that immunotherapies targeting MMP-14 can limit immune suppression, tumor progression, and metastasis in triple-negative breast cancer.


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