Preventing vaccinia virus class-I epitopes presentation by HSV-ICP47 enhances the immunogenicity of a TAP-independent cancer vaccine epitope.

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-1(27-35) 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.

• Authors: Nermin Raafat, Charlotte Sadowski-Cron, Chantal Mengus, Michael Heberer, Giulio C Spagnoli, Paul Zajac
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 5 Pg. E659-69 (Sep 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 22116674 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 UICC.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters
• Antigens, Viral
• B7-1 Antigen
• CD44 protein, human
• Cancer Vaccines
• Cytokines
• Epitopes
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• HLA-DR Antigens
• Hyaluronan Receptors
• ICP47 protein, Herpes simplex virus
• Immediate-Early Proteins
• MART-1 Antigen
• TAP1 protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Antigen Presentation
• Antigen-Presenting Cells (immunology)
• Antigens, Viral (immunology)
• B7-1 Antigen
• Cancer Vaccines (immunology)
• Cell Proliferation
• Cells, Cultured
• Cytokines
• Endoplasmic Reticulum
• Epitopes (immunology)
• Fibroblasts (cytology, immunology, metabolism)
• Genetic Vectors
• HLA-A2 Antigen (immunology)
• HLA-DR Antigens
• Humans
• Hyaluronan Receptors
• Immediate-Early Proteins (genetics, immunology, metabolism)
• MART-1 Antigen (immunology, metabolism)
• Melanoma (immunology, metabolism, pathology)
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccinia virus (immunology)