Remodeling of the epitope repertoire of a candidate idiotype vaccine by targeting to lysosomal degradation in dendritic cells

Martorelli, Debora, Coppotelli, Giuseppe, Muraro, Elena, Dolcetti, Riccardo and Masucci, Maria G. (2012) Remodeling of the epitope repertoire of a candidate idiotype vaccine by targeting to lysosomal degradation in dendritic cells. Cancer Immunology, Immunotherapy, 61 6: 881-892. doi:10.1007/s00262-011-1157-5


Author Martorelli, Debora
Coppotelli, Giuseppe
Muraro, Elena
Dolcetti, Riccardo
Masucci, Maria G.
Title Remodeling of the epitope repertoire of a candidate idiotype vaccine by targeting to lysosomal degradation in dendritic cells
Journal name Cancer Immunology, Immunotherapy   Check publisher's open access policy
ISSN 0340-7004
1432-0851
Publication date 2012-06
Year available 2011
Sub-type Article (original research)
DOI 10.1007/s00262-011-1157-5
Open Access Status Not yet assessed
Volume 61
Issue 6
Start page 881
End page 892
Total pages 12
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Abstract The generation of efficacious vaccines against self-antigens expressed in tumor cells requires breakage of tolerance, and the refocusing of immune responses toward epitopes for which tolerance may not be established. While the presentation of tumor antigens by mature dendritic cells (mDC) may surpass tolerance, broadening of the antigenic repertoire remains an issue. We report that fusion of the candidate idiotype vaccine IGKV3-20 to the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen (EBNA)-1 inhibits degradation by the proteasome and redirects processing to the lysosome. mDCs transduced with a recombinant lentivirus encoding the chimeric idiotype efficiently primed CD4+ and CD8+ cytotoxic T-cell (CTL) responses that lysed autologous blasts expressing IGKV3-20 or pulsed with IGKV3-20 synthetic peptides, and HLA-matched IGKV3-20-positive tumor cell lines. Comparison of the cytotoxic response of CD4+ and CD8+ T lymphocytes activated by mDCs expressing the wild-type or chimeric IGKV3-20 reveled largely non-overlapping epitope repertoires in both CD4+ and CD8+ effectors. Thus, fusion to the GAr may provide an effective means to broaden the immune response to an endogenous protein by promoting the presentation of antigenic epitopes that require a lysosome-dependent processing step.
Keyword Dendritic cell
Epitope choice
Gly-Ala repeat
Idiotype vaccine
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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