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Tumor Immunology
Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope
Article first published online: 3 JAN 2012
DOI: 10.1002/ijc.27362
Copyright © 2011 UICC
Additional Information
How to Cite
Raafat, N., Sadowski-Cron, C., Mengus, C., Heberer, M., Spagnoli, G. C. and Zajac, P. (2012), Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope. Int. J. Cancer, 131: E659–E669. doi: 10.1002/ijc.27362
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Tel.: 0041-0-61-265-2330, Fax: 0041-0-61-265-3990
Publication History
- Issue published online: 27 JUN 2012
- Article first published online: 3 JAN 2012
- Accepted manuscript online: 24 NOV 2011 09:54AM EST
- Manuscript Accepted: 8 NOV 2011
- Manuscript Received: 8 APR 2011
Funded by
- Egyptian Ministry of Education (Cairo, Egypt)
- Freiwilligen Akademischen Gesellschaft (Basel, Switzerland)
- Department of Surgery from the University Hospital of Basel (Basel, Switzeland)
- Sino Swiss Science and Technology Cooperation
Keywords:
- ICP47;
- vaccinia virus;
- viral vectors;
- cancer vaccines
Abstract
Herpes simplex virus protein ICP47, encoded by US12 gene, strongly downregulates major histocompatibility complex (MHC) class-I antigen restricted presentation by blocking transporter associated with antigen processing (TAP) protein. To decrease viral vector antigenic immunodominance and MHC class-I driven clearance, we engineered recombinant vaccinia viruses (rVV) expressing ICP47 alone (rVV-US12) or together with endoplasmic reticulum (ER)-targeted Melan-A/MART-127–35 model tumor epitope (rVV-MUS12). In this study, we show that antigen presenting cells (APC), infected with rVV-US12, display a decreased ability to present TAP dependent MHC class-I restricted viral antigens to CD8+ T-cells. While HLA class-I cell surface expression is strongly downregulated, other important immune related molecules such as CD80, CD44 and, most importantly, MHC class-II are unaffected. Characterization of rVV-MUS12 infected cells demonstrates that over-expression of a TAP-independent peptide, partially compensates for ICP47 induced surface MHC class-I downregulation (30% vs. 70% respectively). Most importantly, in conditions where clearance of infected APC by virus-specific CTL represents a limiting factor, a significant enhancement of CTL responses to the tumor epitope can be detected in cultures stimulated with rVV-MUS12, as compared to those stimulated by rVV-MART alone. Such reagents could become of high relevance in multiple boost protocols required for cancer immunotherapy, to limit vector-specific responsiveness.