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- Title
Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity.
- Authors
Renaudet, Olivier; Dasgupta, Gargi; Bettahi, Ilham; Shi, Alda; Nesburn, Anthony B.; Dumy, Pascal; BenMohamed, Lbachir
- Abstract
Background: Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and Tcell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glycolipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined. Methods/Principal Findings: 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 (HER420-429). 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 α-GalNAc molecules. The resulting HER glycopeptide (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 HER420-429-specific IFN-γ 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). Significance: These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers.
- Subjects
LIPOPROTEINS; LIPOPROTEIN lipase; FATTY acids; ANTINEOPLASTIC agents; VACCINES; IMMUNOGENETICS; ANTIBODY diversity; HUMAN immunogenetics; B cells; T cells
- Publication
PLoS ONE, 2010, Vol 5, Issue 6, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0011216