title: Immunogenic HSV-mediated oncolysis shapes the antitumor immune response and contributes to therapeutic efficacy.
abstract: Within the oncolytic virus field, the extent of virus replication that is essential for immune stimulation to control tumor growth remains unresolved. Using infected cell protein 0 (ICP0)-defective oncolytic Herpes simplex virus type 1 (HSV-1) and HSV-2 viruses (dICP0 and dNLS) that show differences in their in vitro replication and cytotoxicity, we investigated the inherent features of oncolytic HSV viruses that are required for potent antitumor activity. In vitro, the HSV-2 vectors showed rapid cytotoxicity despite lower viral burst sizes compared to HSV-1 vectors. In vivo, although both of the dICP0 vectors initially replicated to a similar level, HSV-1 dICP0 was rapidly cleared from the tumors. In spite of this rapid clearance, HSV-1 dICP0 treatment conferred significant survival benefit. HSV-1 dICP0-treated tumors showed significantly higher levels of danger-associated molecular patterns that correlated with higher numbers of antigen-presenting cells within the tumor and increased antigen-specific CD8+ T-cell levels in the peripheral blood. This study suggests that, at least in the context of oncolytic HSV, the initial stages of immunogenic virus replication leading to activation of antitumor immunity are more important than persistence of a replicating virus within the tumor. This knowledge provides important insight for the design of therapeutically successful oncolytic viruses.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Workenhe
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Graydon
authors.initials: G
authors.lastname: Simmons
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Pol
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.affiliation: Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Halford
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D024243:HMGB1 Protein / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D018139:Simplexvirus / Q000235:genetics* / Q000276:immunology*; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D024243:HMGB1 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases