title: Robo4 vaccines induce antibodies that retard tumor growth.
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.
authors.affiliation: Institute for Biomedical Research, Schools of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhuang
authors.forename: Forhad
authors.initials: F
authors.lastname: Ahmed
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Ferguson
authors.forename: Jane C
authors.initials: JC
authors.lastname: Steele
authors.forename: Neil M
authors.initials: NM
authors.lastname: Steven
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Nagy
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Heath
authors.forename: Kai-Michael
authors.initials: KM
authors.lastname: Toellner
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002846:Chromatography, Affinity; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000276:immunology*; D010206:Papain; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000276:immunology / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D007141:Immunoglobulin Fc Fragments; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C540792:Robo4 protein, mouse; D014614:Vaccines, Synthetic; D010206:Papain