title: Immune and anticancer responses elicited by fully synthetic aberrantly glycosylated MUC1 tripartite vaccines modified by a TLR2 or TLR9 agonist.
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 (Pam3 CysSK4 ) or TLR9 (CpG-ODN 1826) agonist. It was found that the Pam3 CysSK4 -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 Pam3 CysSK4 , 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.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602 (USA).
authors.forename: Abu-Baker M
authors.initials: AB
authors.lastname: Abdel-Aal
authors.forename: Vani
authors.initials: V
authors.lastname: Lakshminarayanan
authors.forename: Pamela
authors.initials: P
authors.lastname: Thompson
authors.forename: Nitin
authors.initials: N
authors.lastname: Supekar
authors.forename: Judy M
authors.initials: JM
authors.lastname: Bradley
authors.forename: Margreet A
authors.initials: MA
authors.lastname: Wolfert
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cohen
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000818:Animals; D001940:Breast / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy*; D019496:Cancer Vaccines / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006020:Glycopeptides / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D006031:Glycosylation; D006801:Humans; D007111:Immunity, Cellular; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014614:Vaccines, Synthetic / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D006020:Glycopeptides; D018396:Mucin-1; D051195:Toll-Like Receptor 2; D051217:Toll-Like Receptor 9; D014614:Vaccines, Synthetic
keywords: adjuvants; cancer; carbohydrates; mucins; peptides; vaccines