Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer
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Julia Femel1, Elisabeth J.M. Huijbers1, Falk Saupe1, Jessica Cedervall1, Lei Zhang2, Pernilla Roswall3, Erik Larsson2, Helena Olofsson2, Kristian Pietras4, Anna Dimberg2, Lars Hellman5 and Anna-Karin Olsson1
1 Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Biomedical Center, Uppsala
2 Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala
3 Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm
4 Department of Laboratory Medicine, Lund University, Medicon Village AB, Lund
5 Department of Cell and Molecular Biology, Uppsala University, Sweden
Anna-Karin Olsson, email:
Keywords: ED-A, immunization, tumor vasculature, therapeutic, cancer vaccine
Received: September 03, 2014 Accepted: October 23, 2014 Published: October 24, 2014
Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies.
Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.
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