Oncogene doi: 10.1038/onc.2010.176
Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma
B K Haller1,2,6, A Br?ve1,2, E Wallgard3,7, P Roswall3, V G Sunkari4, U Mattson5, D Halleng?rd1,2, S-B Catrina4, M Hellstr?m5,7 and K Pietras3
1Department of Virology, Swedish Institute for Infectious Disease Control, Stockholm, Sweden
2Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
3Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
4Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
5Bioinvent International, Lund, Sweden
6Current address: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
7Current address: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
The Notch ligand delta-like ligand 4 (DLL4) is an essential component expressed by endothelial tip cells during angiogenic sprouting. We have described a conceptually novel therapeutic strategy for targeting tumor angiogenesis and endothelial tip cells based on DNA vaccination against DLL4. Immunization with DLL4-encoding plasmid DNA by in vivo electroporation severely retarded the growth of orthotopically implanted mammary carcinomas in mice by induction of a nonproductive angiogenic response. Mechanistically, vaccination brought about a break in tolerance against the self-antigen, DLL4, as evidenced by the production of inhibitory and inherently therapeutic antibodies against mouse DLL4. Importantly, no evidence for a delayed wound healing response, or for toxicity associated with pharmacological blockade of DLL4 signaling, was noted in mice immunized with the DLL4 vaccine. We have thus developed a well-tolerated DNA vaccination strategy targeting the endothelial tip cells and the antigen DLL4 with proven therapeutic efficacy in mouse models of mammary carcinoma; a disease that has been reported to dramatically induce the expression of DLL4. Conceivably, induction of immunity toward principal mediators of pathological angiogenesis could provide protection against recurrent malignant disease in the adjuvant setting.