Abstract
The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer therapy. Here we show that immunotherapy of tumors using fixed xenogeneic whole endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumor-bearing mice. Furthermore, autoreactive immunity targeting to microvessels in solid tumors was induced and was probably responsible for the anti-tumor activity. These observations may provide a new vaccine strategy for cancer therapy through the induction of an autoimmune response against the tumor endothelium in a cross-reaction.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst. 82, 4–6 (1990).
Ferrara, N. & Alitalo, K. Clinical application of angiogenic growth factors and their inhibitors. Nature Med. 5, 1359–1364 (1999)
Risau, W. Mechanism of angiogenesis. Nature 386, 671 –674 (1997)
Zetter, B.R. Angiogenesis and tumor metastasis. Annu. Rev. Med. 49, 407–424 (1998)
Cao, R., et al. Suppression of angiogenesis and tumor growth by the inhibitor K1-5 generated by plasmin-mediated proteolysis. Proc. Natl. Acad. Sci. USA 96, 5728–5733 ( 1999)
Bicknell, R. in Tumor Angiogenesis. (eds. Bicknell, R., Lewis, C.E. & Ferrara. N.) 19–28 (Oxford University Press, Oxford, 1997).
O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997)
Kerbel. R. S. A cancer therapy resistant to resistant. Nature 390 , 335 (1997)
Fidler. I.J. & Ellis, L. M. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 79, 185–188 (1994).
Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377–379 (1998);
Fan, T.P., Jaggar, R. & Bicknell, R. Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol. Sci. 16, 57–66 ( 1995)
Kim, K.J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature 362, 841–844 (1993)
Hanahan D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. J. Natl. Cancer Inst. 88, 1091–1092 ( 1996).
Quinn, T.P., Peters, K.G., De Vries, C., Ferrara, N. & Williams, L.T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc. Natl. Acad. Sci. USA 90, 7533–7537 (1993)
Djaffar, I. et al. A new alternative transcript encodes a 60 kDa truncated form of integrin beta 3. Biochem. J. 15, 69– 74 (1994)
Eichmann, A., Marcelle C., Breant, C. Le Douarin, N.M. Molecular cloning of Quek 1 and 2, two quail vascular endothelial growth factor (VEGF) receptor-like molecules . Gene 174, 3–8 (1996)
Barth, R.J.J., Bock, S.N., Mule, J.J. & Rosenberg, S.A. Unique murine tumor-associated antigens identified by tumor infiltrating lymphocytes. J. Immunol. 144, 1531–1537 (1990).
Boon, T., Coulie, P.G. & Van den Eynde, B. Tumor antigens recognized by T cells. Immunol. Today 18, 267–268 ( 1997).
Rosenberg, S.A. Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol. Today 18, 175– 178 (1997).
Murray, J.S. How the MHC selects Th1/Th2 immunity. Immunol. Today 19, 157–163 (1998).
Romagnani, S. The Th1/Th2 paradigm. Immunol. Today 18, 263–266 (1997).
Ohashi, P.S. T cell selection and autoimmunity: flexibility and tuning. Curr. Opin. Immunol. 8, 808–814 (1996).
Kumar, V., Stellrecht, K. & Sercarz, E. Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J. Exp. Med. 184, 1609– 1617 (1996).
De Silva, H.D., Van Driel, I.R., La Gruta, N., Toh, B.H. & Gleeson, P.A. CD4+ T cells, but not CD8+ T cells, are required for the development of experimental autoimmune gastritis. Immunology 93, 405–408 ( 1998).
Marconcini, L. et al. C-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc. Natl. Acad. Sci. USA 96, 9671–9676 (1999).
Mandriota, S.J. et al. Transforming growth factor β1 down-regulates vascular endothelial growth factor receptor 2/fik-1 expression in vascular endothelial cells. J. Biol. Chem. 271, 11500– 11505 (1996).
Yeh, C.H., Peng H.C. & Huang T.F. Cytokines modulate integrin αvβ3-mediated human endothelial cell adhesion and calcium signaling. Exp. Cell Res. 251, 57–66 ( 1999).
Soker, S. et al. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-endoded domain . J. Biol. Chem. 271, 5761– 5767 (1996).
Piossek, C. et al. Vascular endothelial growth factor (VEGF) receptor II-derived peptides inhibit VEGF. J. Biol. Chem. 274, 5612–5619 (1999).
Cheifetz, S. et al. Endoglin is a component of the transforming growth factor-b receptor system in human endothelial cells. J. Biol. Chem. 267, 19027–19030 (1992).
Jones, N. et al. Identification of Tek/Tie 2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J. Biol. Chem. 274, 30896–30905 ( 1999).
Witzenbichler, B. et al. Chemotactic properties of angiopoietin-1 and –2, ligands for the endothelial-specific receptor tyrosine kinase Tie-2. J. Biol. Chem. 273, 18514–18521 (1998).
Eliceiri, B.P & Cheresh, D.A. The role αv integrins during angiogenesis: insights into potential mechanisms of action and clinical development . J. Clin. Invest. 103, 1227– 1230 (1999).
Smith, J.W. et al. Integrin avb3-ligand interaction. Identification of a heterodimeric RGD binding Site on the vitronectin receptor. J. Biol. Chem. 265, 2168–2172 (1990).
Lin, E.C., Carron, C.P., Meyer, D.M. & Smith, J.W. A series of function blocking antibodies against the αvβ3 integrin bind allosteric to the ligand binding site and induce ligand dissociation . Cell Adhes. Commmun. 6, 451– 464 (1998).
Beekhuizen, H. et al. Infection of human vascular endothelial cells with staphylococcus aureus induces hyperadhesiveness for human monocytes and granulocytes. J. Immunol. 158, 774–782 (1997).
Wei, Y.-Q. et al. Induction of apoptosis by quercetin: involvement of heat shock protein. Cancer Res. 54, 4952– 4957 (1994).
Pulendran B., et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl. Acad. Sci. USA 96, 1036–1041 ( 1999).
Schellekens, G. A. et al. Citrulline is an essential constitute of antigenic determinants recognised by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).
Horton, H. M. et al. A gene therapy for cancer using intramuscular injection of plasmid DNA encoding interferon α. Proc. Natl. Acad. Sci. USA 96, 1553–1558 ( 1999).
Pan, Z-K. et al. A recombinant Listeria monocytogenes vaccine expressing a model tumor antigen protects mice against lethal tumor antigen protects mice against lethal tumor cell challenge and causes regression of established tumours. Nature Med. 1, 471– 477 (1995).
Ortega, S. et al. Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc. Natl. Acad. Sci. USA 95, 5672–5677 (1998).
Wei, Y.-Q. et al. Induction of autologous tumor killing by heat treatment of fresh human tumor cells: involvement of γδ T cells and heat shock protein 70. Cancer Res. 56, 1104– 1110 (1996).
Volpert, O.V. et al. A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proc. Natl. Acad. Sci. USA 95, 6343–6348 (1998).
Pummerer, C.L, et al. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J. Clin. Invest. 97, 2057–2062 (1996).
Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).
Acknowledgements
This work was supported by the National Outstanding Young Scientist Foundation of China, the National Natural Sciences Foundation of China, the National 973 Project and the Foundation for University Key Teacher.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wei, Yq., Wang, Qr., Zhao, X. et al. Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine . Nat Med 6, 1160–1166 (2000). https://doi.org/10.1038/80506
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/80506
This article is cited by
-
X-ray Irradiated Vaccine Confers protection against Pneumonia caused by Pseudomonas Aeruginosa
Scientific Reports (2016)
-
Endothelial Cords Promote Tumor Initial Growth prior to Vascular Function through a Paracrine Mechanism
Scientific Reports (2016)
-
Fusion with human lung cancer cells elongates the life span of human umbilical endothelial cells and enhances the anti-tumor immunity
Journal of Cancer Research and Clinical Oncology (2016)
-
Dendritic cells loading autologous tumor lysate promote tumor angiogenesis
Tumor Biology (2016)
-
Cancer anti-angiogenesis vaccines: Is the tumor vasculature antigenically unique?
Journal of Translational Medicine (2015)