Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Laboratory of Cellular and Molecular Immunology, The Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, California, USA.
PLoS ONE (Impact Factor: 3.23). 06/2010; 5(6):e11216. DOI: 10.1371/journal.pone.0011216
Source: PubMed


Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.
We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).
These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers.

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    • "Later a three-component GLP vaccine by Ingale and coworkers (a three palmitic acid Pam3CSK4 moiety, a CD4+ and a B-cell epitope) showed induction of strong tumor-specific IgG responses [20]. Recently, Renaudet and coworkers showed a four-component HER-GLP vaccine construct (one CD4+ T-cell epitope, one OVA CD8+ T-cell epitope, one carbohydrate B-cell epitope and a built-in palmitic acid adjuvant) inhibited the tumor growth in HER-GLP immunized mice [21]. "
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