title: NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors.
abstract: The role of the immune response to oncolytic Herpes simplex viral (oHSV) therapy for glioblastoma is controversial because it might enhance or inhibit efficacy. We found that within hours of oHSV infection of glioblastomas in mice, activated natural killer (NK) cells are recruited to the site of infection. This response substantially diminished the efficacy of glioblastoma virotherapy. oHSV-activated NK cells coordinated macrophage and microglia activation within tumors. In vitro, human NK cells preferentially lysed oHSV-infected human glioblastoma cell lines. This enhanced killing depended on the NK cell natural cytotoxicity receptors (NCRs) NKp30 and NKp46, whose ligands are upregulated in oHSV-infected glioblastoma cells. We found that HSV titers and oHSV efficacy are increased in Ncr1(-/-) mice and a Ncr1(-/-) NK cell adoptive transfer model of glioma, respectively. These results demonstrate that glioblastoma virotherapy is limited partially by an antiviral NK cell response involving specific NCRs, uncovering new potential targets to enhance cancer virotherapy.
authors.affiliation: Medical Scientist Training Program, Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Alvarez-Breckenridge
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Richard
authors.initials: R
authors.lastname: Price
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.forename: Jason
authors.initials: J
authors.lastname: Pradarelli
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Shun
authors.initials: S
authors.lastname: He
authors.forename: Jayson
authors.initials: J
authors.lastname: Hardcastle
authors.forename: Soledad A
authors.initials: SA
authors.lastname: Fernandez
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Sean E
authors.initials: SE
authors.lastname: Lawler
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
mesh_terms: D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000378:metabolism*; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000379:methods*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus; D014709:Vero Cells
chemical_list: D000950:Antigens, Ly; D017931:DNA Primers; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; C118384:Ncr1 protein, mouse