title: Systemic CD8+ T cell-mediated tumoricidal effects by intratumoral treatment of oncolytic herpes simplex virus with the agonistic monoclonal antibody for murine glucocorticoid-induced tumor necrosis factor receptor.
abstract: Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry. Intratumoral administration of HF10 in combination with DTA-1 at a low dose resulted in a more vigorous attenuation of growth of the untreated contralateral as well as the treated tumors than treatment with either HF10 or DTA-1 alone. An accumulation of CD8(+) T cells, including tumor- and herpes simplex virus type-1-specific populations, and a decrease in the number of CD4(+) Foxp3(+) T regulatory cells were seen in both HF10- and DTA-1-treated tumors. Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages. These results indicated the potential therapeutic efficacy of a glucocorticoid-induced tumor necrosis factor receptor-specific monoclonal antibody in oncolytic virotherapy at local tumor sites.
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Mikiya
authors.initials: M
authors.lastname: Ishihara
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Seo
authors.affiliation: Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muraoka
authors.affiliation: Gene Medicine Business Unit, Takara Bio Inc., Shiga, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Gene Medicine Business Unit, Takara Bio Inc., Shiga, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D018259:Herpesvirus 1, Human / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018124:Receptors, Tumor Necrosis Factor
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