Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo

Henry Ogbomo, Franz J. Zemp, Xueqing Lun, Jiqing Zhang, Danuta Stack, Masmudur M. Rahman, Grant Mcfadden, Christopher H. Mody, Peter A. Forsyth

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Article numbere66825
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - Jun 10 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Ogbomo, H., Zemp, F. J., Lun, X., Zhang, J., Stack, D., Rahman, M. M., Mcfadden, G., Mody, C. H., & Forsyth, P. A. (2013). Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo. PloS one, 8(6), [e66825]. https://doi.org/10.1371/journal.pone.0066825