title: UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells.
abstract: Herein we demonstrate that oncolytic herpes simplex virus-1 (HSV-1) potently activates human peripheral blood mononuclear cells (PBMCs) to lyse leukemic cell lines and primary acute myeloid leukemia samples, but not healthy allogeneic lymphocytes. Intriguingly, we found that UV light-inactivated HSV-1 (UV-HSV-1) is equally effective in promoting PBMC cytolysis of leukemic cells and is 1000- to 10 000-fold more potent at stimulating innate antileukemic responses than UV-inactivated cytomegalovirus, vesicular stomatitis virus, reovirus, or adenovirus. Mechanistically, UV-HSV-1 stimulates PBMC cytolysis of leukemic cells, partly via Toll-like receptor-2/protein kinase C/nuclear factor-κB signaling, and potently stimulates expression of CD69, degranulation, migration, and cytokine production in natural killer (NK) cells, suggesting that surface components of UV-HSV-1 directly activate NK cells. Importantly, UV-HSV-1 synergizes with interleukin-15 (IL-15) and IL-2 in inducing activation and cytolytic activity of NK cells. Additionally, UV-HSV-1 stimulates glycolysis and fatty acid oxidation-dependent oxygen consumption in NK cells, but only glycolysis is required for their enhanced antileukemic activity. Last, we demonstrate that T cell-depleted human PBMCs exposed to UV-HSV-1 provide a survival benefit in a murine xenograft model of human acute myeloid leukemia (AML). Taken together, our results support the preclinical development of UV-HSV-1 as an adjuvant, alone or in combination with IL-15, for allogeneic donor mononuclear cell infusions to treat AML.
authors.affiliation: Programa de Investigacion e Innovacion en Leucemia Aguda y Cronica, Bogotá, Colombia; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Ismael
authors.initials: I
authors.lastname: Samudio
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Hila
authors.initials: H
authors.lastname: Shaim
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Elyse
authors.initials: E
authors.lastname: Hofs
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Mor
authors.initials: M
authors.lastname: Ngom
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Luke
authors.initials: L
authors.lastname: Bu
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Liu
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Jason T C
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Suzan
authors.initials: S
authors.lastname: Imren
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Vivian
authors.initials: V
authors.lastname: Lam
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Grace F T
authors.initials: GF
authors.lastname: Poon
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghaedi
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Fumio
authors.initials: F
authors.lastname: Takei
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Keith
authors.initials: K
authors.lastname: Humphries
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Jia
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada;
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
mesh_terms: D015550:Cell Degranulation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D005260:Female; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D011493:Protein Kinase C / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014466:Ultraviolet Rays; D038301:Virus Inactivation / Q000528:radiation effects*
chemical_list: C569274:IL15 protein, human; C508594:IL2 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D011493:Protein Kinase C