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Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2014 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, 12418-12427 p.Article in journal (Refereed) Published
Abstract [en]

Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

Place, publisher, year, edition, pages
2014. Vol. 5, no 23, 12418-12427 p.
Keyword [en]
ED-A, immunization, tumor vasculature, therapeutic, cancer vaccine
National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-229544ISI: 000348037700049PubMedID: 25360764OAI: oai:DiVA.org:uu-229544DiVA: diva2:736951
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis
Open this publication in new window or tab >>Therapeutic Cancer Vaccines Targeting Molecules Associated with Tumor Angiogenesis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Induction of an endogenous antibody response by therapeutic vaccination could provide an alternative to cost-intensive monoclonal antibody-based treatments for cancer. Since the target of a cancer vaccine will most likely be a self-antigen, self-tolerance of the immune system must be circumvented. Using fusion proteins consisting of the self-antigen to be targeted and a part derived from a foreign antigen, it is possible to break tolerance against the self-antigen. Furthermore, a potent adjuvant is required to support an immune response against a self-molecule. Currently no adjuvant suitable for this purpose is approved for use in humans.

This thesis describes the development of a therapeutic vaccine targeting the vasculature of tumors. As tumor cells have developed strategies to escape immune surveillance, targeting of molecules associated with the tumor stroma is an interesting alternative. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin and the glycan-binding protein galectin-1 are selectively expressed during events of tumor angiogenesis. We have designed recombinant proteins to target ED-B, ED-A and galectin-1, containing bacterial thioredoxin (TRX) as a non-self part, resulting in TRX-EDB, TRX-EDA and TRX-Gal-1. Vaccination against ED-B induced anti-ED-B antibodies and inhibited growth of subcutaneous fibrosarcoma. Immunization against ED-A decreased tumor burden and reduced the number of lung metastases in the MMTV-PyMT model for metastatic mammary carcinoma in a therapeutic setting. Analysis of the tumor tissue from ED-B and ED-A-immunized mice indicated an attack of the tumor vasculature by the immune system. Finally, we show that galectin-1 immunization reduced tumor burden and increased leukocyte numbers in the tumor tissue. Galectin-1 is pro-angiogenic and immunosuppressive, and therefore allows simultaneous targeting of fundamental characteristics of tumorigenesis. We furthermore show that the biodegradable squalene-based Montanide ISA 720 combined with CpG oligo 1826 (M720/CpG) is at least as potent as Freund’s adjuvant with respect to breaking self-tolerance, when comparing several immunological parameters. Freund’s is a potent but toxic adjuvant used in the majority of preclinical studies.

The work presented in this thesis shows that therapeutic cancer vaccines targeting the tumor vasculature are a feasible and promising approach for cancer therapy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1017
Keyword
tumor, therapeutic, cancer vaccine, angiogenesis, vasculature, fibronectin, galectin-1
National Category
Cancer and Oncology Immunology in the medical area Cell and Molecular Biology
Research subject
Medical Cell Biology; Oncology; Biomedical Laboratory Science; Medical Science
Identifiers
urn:nbn:se:uu:diva-229572 (URN)978-91-554-8998-4 (ISBN)
Public defence
2014-09-26, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-09-03 Created: 2014-08-11 Last updated: 2014-09-08

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Femel, JuliaSaupe, FalkCedervall, JessicaZhang, LeiLarsson, ErikDimberg, AnnaHellman, LarsOlsson, Anna-Karin

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Femel, JuliaSaupe, FalkCedervall, JessicaZhang, LeiLarsson, ErikDimberg, AnnaHellman, LarsOlsson, Anna-Karin
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Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabVascular BiologyMolecular and Morphological PathologyDepartment of Immunology, Genetics and PathologyChemical Biology
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OncoTarget
Cancer and OncologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

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