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Immunology |
1 Department of Immunology, Imperial College, London, United Kingdom; 2 Stanford Tumor Glycomics Laboratory, Department of Genetics and 3 Neurology and Neuroscience, Stanford University School of Medicine, Stanford, California; 4 Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland; and 5 NIH Research Biomedical Research Centre, Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom
Requests for reprints: Gavin R. Screaton, Department of Immunology, Commonwealth Building, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-3201; Fax: 44-20-8383-3203; E-mail: g.screaton{at}imperial.ac.uk.
Key Words: Fas ligand • tumor • monoclonal antibody • glycan
Abnormal glycosylation is one of the hallmarks of the cancer cell and is associated with tumor invasion and metastasis. The development of tumor-associated carbohydrate antigen (TACA) vaccines has been problematic due to poor immunogenicity. However, when appropriate targets can be identified, passive immunization with monoclonal antibodies (mAbs) directed against TACAs has been shown to have antitumor activity. Fas ligand (FasL) is a transmembrane protein that induces apoptosis in cells expressing its receptor, Fas. When grafted into mice, FasL-expressing tumor cells break immunologic tolerance to self-antigens and induce antibody-mediated tumor immunity. Here, five IgM mAbs were produced from mice vaccinated with FasL-expressing B16F10 mouse melanoma cells. They recognize various syngeneic and allogeneic murine tumor cell lines. One mAb, TM10, recognizes a range of human tumor cell lines, including melanoma, prostate, and ovarian cancer. It does not bind to untransformed cells. The epitopes recognized by all the mAbs were carbohydrates expressed on proteins. Using carbohydrate microarrays, the antigenic targets of TM10 were found to be high-mannose core structures of N-linked glycans. In normal cells, high-mannose clusters are hidden by extensive saccharide branching but they become exposed in cancer cells as a result of abnormal glycosylation pathways. Vaccination with FasL-expressing tumors therefore enables the immune system to break tolerance to self-antigens, allowing identification of novel TACAs that can form the basis of future humoral anticancer therapy. [Cancer Res 2009;69(5):2018–25]
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