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Targeting galectin-1 by vaccination suppresses tumor growth and promotes leukocyte recruitment to the tumor tissue
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
galectin-1, immunization, tumor angiogenesis, therapeutic, cancer vaccine
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-229569OAI: oai:DiVA.org:uu-229569DiVA: diva2:736953
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2014-09-08
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)
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Supervisors
Available from: 2014-09-03 Created: 2014-08-11 Last updated: 2014-09-08

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Femel, Julia

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