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: Abu-Baker M Abdel-Aal, Vani Lakshminarayanan, Pamela Thompson, Nitin Supekar, Judy M Bradley, Margreet A Wolfert, Peter A Cohen, Sandra J Gendler, Geert-Jan Boons
• Journal: Chembiochem : a European journal of chemical biology (Chembiochem) Vol. 15 Issue 10 Pg. 1508-13 (Jul 07 2014) ISSN: 1439-7633 [Electronic] Germany
• PMID: 24890740 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Adjuvants, Immunologic
• Cancer Vaccines
• Glycopeptides
• Mucin-1
• Toll-Like Receptor 2
• Toll-Like Receptor 9
• Vaccines, Synthetic

Topics

• Adjuvants, Immunologic (chemistry, therapeutic use)
• Amino Acid Sequence
• Animals
• Breast (immunology)
• Breast Neoplasms (immunology, therapy)
• Cancer Vaccines (chemistry, immunology, therapeutic use)
• Cell Line, Tumor
• Female
• Glycopeptides (chemistry, immunology, therapeutic use)
• Glycosylation
• Humans
• Immunity, Cellular
• Immunization
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Mucin-1 (chemistry, immunology, therapeutic use)
• T-Lymphocytes, Cytotoxic (immunology)
• Toll-Like Receptor 2 (agonists)
• Toll-Like Receptor 9 (agonists)
• Vaccines, Synthetic (chemistry, immunology, therapeutic use)