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Robo4 vaccines induce antibodies that retard tumor growth

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Abstract

Tumor endothelial specific expression of Robo4 in adults identifies this plasma membrane protein as an anti-cancer target for immunotherapeutic approaches, such as vaccination. In this report, we describe how vaccination against Robo4 inhibits angiogenesis and tumor growth. To break tolerance to the auto-antigen Robo4, mice were immunised with the extracellular domain of mouse Robo4, fused to the Fc domain of human immunoglobulin within an adjuvant. Vaccinated mice show a strong antibody response to Robo4, with no objectively detectable adverse effects on health. Robo4 vaccinated mice showed impaired fibrovascular invasion and angiogenesis in a rodent sponge implantation assay, as well as a reduced growth of implanted syngeneic Lewis lung carcinoma. The anti-tumor effect of Robo4 vaccination was present in CD8 deficient mice but absent in B cell or IgG1 knockout mice, suggesting antibody dependent cell mediated cytotoxicity as the anti-vascular/anti-tumor mechanism. Finally, we show that an adjuvant free soluble Robo4-carrier conjugate can retard tumor growth in carrier primed mice. These results point to appropriate Robo4 conjugates as potential anti-angiogenic vaccines for cancer patients.

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Acknowledgments

This work was funded by Cancer Research UK Grant Number C4719/A7825 awarded to Roy Bicknell.

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Authors and Affiliations

  1. Institute for Biomedical Research, Schools of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Xiaodong Zhuang, Forhad Ahmed, Yang Zhang, Henry J. Ferguson, Victoria L. Heath, Kai-Michael Toellner & Roy Bicknell

  2. MRC Centre for Immune Regulation, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Yang Zhang & Kai-Michael Toellner

  3. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Xiaodong Zhuang, Jane C. Steele, Neil M. Steven & Roy Bicknell

  4. Division of Neurodegeneration, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Zsuzsanna Nagy

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  1. Xiaodong Zhuang
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  2. Forhad Ahmed
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  10. Roy Bicknell
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Correspondence to Roy Bicknell.

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Zhuang, X., Ahmed, F., Zhang, Y. et al. Robo4 vaccines induce antibodies that retard tumor growth. Angiogenesis 18, 83–95 (2015). https://doi.org/10.1007/s10456-014-9448-z

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