Myxoma virus infection promotes NK lysis of malignant gliomas in vitro and in vivo

PLoS One. 2013 Jun 10;8(6):e66825. doi: 10.1371/journal.pone.0066825. Print 2013.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain Neoplasms / immunology
  • Brain Neoplasms / prevention & control*
  • Brain Neoplasms / virology
  • Female
  • Glioma / immunology
  • Glioma / prevention & control*
  • Glioma / virology
  • Histocompatibility Antigens Class I / chemistry
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / pathology
  • Mice
  • Mice, SCID
  • Myxoma virus / physiology
  • Oncolytic Virotherapy*
  • Poxviridae Infections / immunology
  • Poxviridae Infections / prevention & control*
  • Poxviridae Infections / virology
  • Tumor Cells, Cultured
  • Tumor Virus Infections / immunology
  • Tumor Virus Infections / prevention & control*
  • Tumor Virus Infections / virology


  • Histocompatibility Antigens Class I