TY - JOUR
T1 - Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo
AU - Ogbomo, Henry
AU - Zemp, Franz J.
AU - Lun, Xueqing
AU - Zhang, Jiqing
AU - Stack, Danuta
AU - Rahman, Masmudur M.
AU - Mcfadden, Grant
AU - Mody, Christopher H.
AU - Forsyth, Peter A.
PY - 2013/6/10
Y1 - 2013/6/10
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0066825
DO - 10.1371/journal.pone.0066825
M3 - Article
C2 - 23762498
AN - SCOPUS:84878852286
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 6
M1 - e66825
ER -