TY - JOUR
T1 - NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors
AU - Alvarez-Breckenridge, Christopher A.
AU - Yu, Jianhua
AU - Price, Richard
AU - Wojton, Jeffrey
AU - Pradarelli, Jason
AU - Mao, Hsiaoyin
AU - Wei, Min
AU - Wang, Yan
AU - He, Shun
AU - Hardcastle, Jayson
AU - Fernandez, Soledad A.
AU - Kaur, Balveen
AU - Lawler, Sean E.
AU - Vivier, Eric
AU - Mandelboim, Ofer
AU - Moretta, Alessandro
AU - Caligiuri, Michael A.
AU - Chiocca, E. Antonio
N1 - Funding Information:
This work was supported by US National Institutes of Health grants 7U01NS061811 (to E.A.C.), CA069246 (to E.A.C.), CA068458 (to M.A.C.), CA095426 (to M.A.C.), TL1RR025753 (to C.A.A.-B.) and CA163205 (to E.A.C., M.A.C. and B.K.). C.A.A.-B. was supported by an American Medical Association Foundation Seed Grant. This work was also supported by the Dardinger Neuro-oncology Laboratory.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870909657&partnerID=8YFLogxK
U2 - 10.1038/nm.3013
DO - 10.1038/nm.3013
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C2 - 23178246
AN - SCOPUS:84870909657
SN - 1078-8956
VL - 18
SP - 1827
EP - 1834
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -
