title: CD8(+) T-cell Immune Evasion Enables Oncolytic Virus Immunotherapy.
abstract: Although counteracting innate defenses allows oncolytic viruses (OVs) to better replicate and spread within tumors, CD8(+) T-cells restrict their capacity to trigger systemic anti-tumor immune responses. Herpes simplex virus-1 (HSV-1) evades CD8(+) T-cells by producing ICP47, which limits immune recognition of infected cells by inhibiting the transporter associated with antigen processing (TAP). Surprisingly, removing ICP47 was assumed to benefit OV immuno-therapy, but the impact of inhibiting TAP remains unknown because human HSV-1 ICP47 is not effective in rodents. Here, we engineer an HSV-1 OV to produce bovine herpesvirus UL49.5, which unlike ICP47, antagonizes rodent and human TAP. Significantly, UL49.5-expressing OVs showed superior efficacy treating bladder and breast cancer in murine models that was dependent upon CD8(+) T-cells. Besides injected subcutaneous tumors, UL49.5-OV reduced untreated, contralateral tumor size and metastases. These findings establish TAP inhibitor-armed OVs that evade CD8(+) T-cells as an immunotherapy strategy to elicit potent local and systemic anti-tumor responses.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pourchet
authors.affiliation: Benevir Biopharm, Gaithersburg, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Fuhrmann
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Karsten A
authors.initials: KA
authors.lastname: Pilones
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA; NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Demaria
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY, USA; NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Frey
authors.affiliation: Benevir Biopharm, Gaithersburg, MD, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mulvey
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, USA; NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Mohr
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002417:Cattle; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology; D057131:Immune Evasion / Q000235:genetics; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000628:therapy; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
chemical_list: C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; C099455:UL49.5 protein, bovine herpesvirus type 1; D014759:Viral Envelope Proteins
keywords: CD8+ T-cell immune evasion; Immunotherapy; Oncolytic virus; TAP inhibitor