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Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma

Oncogene volume 29, pages 4276–4286 (2010)Cite this article

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Abstract

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.

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Acknowledgements

We are grateful to Cyto Pulse Sciences, Inc., Glen Burnie, MD, USA for providing the technology for in vivo electroporation. This study was supported by grants to KP from the Swedish Cancer Society (Young Investigator Award and project grant), the Swedish Research Council (including a Linnaeus grant for the STARGET consortium), by a strategic grant from the Karolinska Institutet Cancer network, Åke Wiberg's foundation and Jeansson's foundation. BKH recieved support from the The Swedish National Board of Health and Welfare, The Alex and Eva Wallström foundation, The Magn. Bergvall foundation and Karolinska Institute Research foundations.

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Author notes

  1. B K Haller

    Present address: 6Current address: Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.,

  2. E Wallgard & M Hellström

    Present address: 7Current address: Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.,

Authors and Affiliations

  1. Department of Virology, Swedish Institute for Infectious Disease Control, Stockholm, Sweden

    B K Haller, A Bråve & D Hallengärd

  2. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    B K Haller, A Bråve & D Hallengärd

  3. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    E Wallgard, P Roswall & K Pietras

  4. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    V G Sunkari & S-B Catrina

  5. Bioinvent International, Lund, Sweden

    U Mattson & M Hellström

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  1. B K Haller
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Correspondence to K Pietras.

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Haller, B., Bråve, A., Wallgard, E. et al. Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma. Oncogene 29, 4276–4286 (2010). https://doi.org/10.1038/onc.2010.176

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