title: Myxoma virus infection promotes NK lysis of malignant gliomas in vitro and in vivo.
abstract: Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R gene product, a viral E3-ubiquitin ligase) and suppressing T cell killing of infected target cells. MHC I down-regulation, however, favors NK cell activation. Brain tumors including gliomas are characterized by high MHC I expression with impaired NK activity. We thus hypothesized that MYXV infection of glioma cells will promote NK cell-mediated recognition and killing of gliomas. We infected human gliomas with MYXV and evaluated their susceptibility to NK cell-mediated cytotoxicity. MYXV enhanced NK cell-mediated killing of glioma cells (U87 cells, MYXV vs. Mock: 51.73% vs. 28.63%, P = .0001, t test; U251 cells, MYXV vs. Mock: 40.4% vs. 20.03%, P .0007, t test). Using MYXV M153R targeted knockout (designated vMyx-M153KO) to infect gliomas, we demonstrate that M153R was responsible for reduced expression of MHC I on gliomas and enhanced NK cell-mediated antiglioma activity (U87 cells, MYXV vs. vMyx-M153KO: 51.73% vs. 25.17%, P = .0002, t test; U251 cells, MYXV vs. vMyx-M153KO: 40.4% vs. 19.27, P = .0013, t test). Consequently, NK cell-mediated lysis of established human glioma tumors in CB-17 SCID mice was accelerated with improved mouse survival (log-rank P = .0072). These results demonstrate the potential for combining MYXV with NK cells to effectively kill malignant gliomas.
authors.affiliation: Departments of Oncology, Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Henry
authors.initials: H
authors.lastname: Ogbomo
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Zemp
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.forename: Jiqing
authors.initials: J
authors.lastname: Zhang
authors.forename: Danuta
authors.initials: D
authors.lastname: Stack
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Mody
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D005260:Female; D005910:Glioma / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009233:Myxoma virus / Q000502:physiology; D050130:Oncolytic Virotherapy; D011213:Poxviridae Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology
chemical_list: D015395:Histocompatibility Antigens Class I