Immune and Anticancer Responses Elicited by Fully Synthetic Aberrantly Glycosylated MUC1 Tripartite Vaccines Modified by a TLR2 or TLR9 Agonist

• Published in: Chembiochem : a European journal of chemical biology Vol. 15; no. 10; pp. 1508 - 1513
• Main Authors: Abdel-Aal, Abu-Baker M., Lakshminarayanan, Vani, Thompson, Pamela, Supekar, Nitin, Bradley, Judy M., Wolfert, Margreet A., Cohen, Peter A., Gendler, Sandra J., Boons, Geert-Jan
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07-07-2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: adjuvants; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - therapeutic use; Amino Acid Sequence; Animals; Breast - immunology; Breast Neoplasms - immunology; Breast Neoplasms - therapy; Cancer; Cancer Vaccines - chemistry; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; carbohydrates; Cell Line, Tumor; Female; Glycopeptides - chemistry; Glycopeptides - immunology; Glycopeptides - therapeutic use; Glycosylation; Humans; Immunity, Cellular; Immunization; Medical research; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mucin-1 - chemistry; Mucin-1 - immunology; Mucin-1 - therapeutic use; mucins; peptides; Rodents; T-Lymphocytes, Cytotoxic - immunology; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 9 - agonists; Vaccines; Vaccines, Synthetic - chemistry; Vaccines, Synthetic - immunology; Vaccines, Synthetic - therapeutic use; carbohydrates; peptides; cancer; mucins; vaccines; adjuvants
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201402077

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.
Synthetic multicomponent vaccines: Immunological evaluations of vaccine candidates, each composed of a glycopeptide, a promiscuous Thelper peptide, and either a TLR2 (Pam3CysSK4) or a TLR9 (CpG‐ODN 1826) agonist, show that the nature of the inbuilt adjuvant significantly impacts the quality of immune responses elicited against a tumor‐associated glycopeptide.