title: 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: Department of Biomedicine, Oncology group, Institute of Surgical Research and Hospital Management, University of Basel, Switzerland.
authors: Nermin
authors: N
authors: Raafat
authors: Charlotte
authors: C
authors: Sadowski-Cron
authors: Chantal
authors: C
authors: Mengus
authors: Michael
authors: M
authors: Heberer
authors: Giulio C
authors: GC
authors: Spagnoli
authors: Paul
authors: P
authors: Zajac
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D018122:B7-1 Antigen; D019496:Cancer Vaccines / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines; D004721:Endoplasmic Reticulum; D000939:Epitopes / Q000276:immunology*; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005822:Genetic Vectors; D015789:HLA-A2 Antigen / Q000276:immunology*; D006684:HLA-DR Antigens; D006801:Humans; D018960:Hyaluronan Receptors; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D058965:MART-1 Antigen / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D018122:B7-1 Antigen; C497483:CD44 protein, human; D019496:Cancer Vaccines; D016207:Cytokines; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D006684:HLA-DR Antigens; D018960:Hyaluronan Receptors; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D058965:MART-1 Antigen; C073119:TAP1 protein, human