Abstract
We have recently demonstrated that linkage of DNA-encoding calreticulin to DNA-encoding human papillomavirus-16 E7 antigen strongly enhances the efficacy of DNA vaccines against E7-expressing tumors in animal models. In this study, as a prelude to clinical translation, we characterized the ability of DNA-encoding calreticulin linked to DNA-encoding E7 antigen to generate HLA-A2-restricted E7-specific CD8+ T-cell responses in HLA-A2 (AAD) transgenic mice, as well as antitumor effects against an E7+ HLA-A2+ tumor cell line, TC-1/A2. Our results show that while vaccination with CRT/E7 DNA generates strong H-2Db-restricted E7 (amino acid (aa)49–57)-specific CD8+ T-cell immune responses in both C57BL/6 and HLA-A2 (AAD) transgenic mice, no such responses were generated to HLA-A2-restricted epitopes in either type of mouse. In contrast, vaccination with DNA-encoding calreticulin linked to DNA encoding a mutant version of E7 with a deleted aa49–57 epitope leads to the generation of an HLA-A2-restricted E7 (aa11–20)-specific CTL response in HLA-A2 (AAD) transgenic mice. More importantly, vaccination with CRT/mtE7 (del aa49–57) DNA protects against a lethal challenge with TC-1/A2 tumor cells in HLA-A2 (AAD) transgenic mice. Furthermore, our in vitro studies demonstrate that the presence of the E7 (aa49–57) epitope does not suppress presentation of the HLA-A2-restricted E7 (aa11–20) epitope through MHC class I molecules. Thus, the predominant E7 aa49–57-specific CD8+ T-cell immune response in HLA-A2 transgenic mice vaccinated with CRT/E7 is likely due to preferred expansion of E7 aa49–57-specific CD8+ T cells in vaccinated mice. These results highlight the importance of epitope immunodominance in the evaluation of immune responses in HLA-A2 (AAD) transgenic mice.
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Acknowledgements
We thank Drs Keerti V Shah and Robert J Kurman for helpful discussions. Calreticulin cDNA was kindly provided by by Dr Marek Michalak (University of Alberta, Edmonton, Canada). We would also like to thank Drs Ralph Hruban, Ken-Yu Lin and Richard Roden for critical review of the manuscript. We would like to thank Mr Bruno Macaes for the preparation of the manuscript. This work was supported by the SPORE (P50 CA098252-02) of the National Cancer Institute.
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Peng, S., Trimble, C., He, L. et al. Characterization of HLA-A2-restricted HPV-16 E7-specific CD8+ T-cell immune responses induced by DNA vaccines in HLA-A2 transgenic mice. Gene Ther 13, 67–77 (2006). https://doi.org/10.1038/sj.gt.3302607
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DOI: https://doi.org/10.1038/sj.gt.3302607
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