Immune and Anticancer Responses Elicited by Fully Synthetic Aberrantly Glycosylated MUC1 Tripartite Vaccines Modified by a TLR2 or TLR9 Agonist |
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| Authors: | Dr Abu‐Baker M Abdel‐Aal Dr Vani Lakshminarayanan Dr Pamela Thompson Nitin Supekar Judy M Bradley Dr Margreet A Wolfert Prof Dr Peter A Cohen Prof Dr Sandra J Gendler Prof Dr Geert‐Jan Boons |
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| Affiliation: | 1. Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602 (USA);2. Department of Biochemistry and Molecular Biology and Immunology, Mayo Clinic College of Medicine and Mayo Clinic Comprehensive Cancer Center, 13400 East Shea Boulevard, Scottsdale, AZ 85259 (USA);3. Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, GA 30602 (USA);4. Department of Hematology and Oncology, Mayo Clinic College of Medicine and Mayo Clinic Comprehensive Cancer Center, 13400 East Shea Boulevard, Scottsdale, AZ 85259 (USA) |
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| Abstract: | The mucin MUC1 is overexpressed and aberrantly glycosylated by many epithelial cancer cells manifested by truncated O‐linked saccharides. Although tumor‐associated MUC1 has generated considerable attention because of its potential for the development of a therapeutic cancer vaccine, it has been difficult to design constructs that consistently induce cytotoxic T‐lymphocytes (CTLs) and ADCC‐mediating antibodies specific for the tumor form of MUC1. We have designed, chemically synthesized, and immunologically examined vaccine candidates each composed of a glycopeptide derived from MUC1, a promiscuous Thelper peptide, and a TLR2 (Pam3CysSK4) or TLR9 (CpG‐ODN 1826) agonist. It was found that the Pam3CysSK4‐containing compound elicits more potent antigenic and cellular immune responses, resulting in a therapeutic effect in a mouse model of mammary cancer. It is thus shown, for the first time, that the nature of an inbuilt adjuvant of a tripartite vaccine can significantly impact the quality of immune responses elicited against a tumor‐associated glycopeptide. The unique adjuvant properties of Pam3CysSK4, which can reduce the suppressive function of regulatory T cells and enhance the cytotoxicity of tumor‐specific CTLs, are likely responsible for the superior properties of the vaccine candidate 1 . |
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| Keywords: | adjuvants cancer carbohydrates mucins peptides vaccines |
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