NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors

Christopher A. Alvarez-Breckenridge, Jianhua Yu, Richard Price, Jeffrey Wojton, Jason Pradarelli, Hsiaoyin Mao, Min Wei, Yan Wang, Shun He, Jayson Hardcastle, Soledad A. Fernandez, Balveen Kaur, Sean E. Lawler, Eric Vivier, Ofer Mandelboim, Alessandro Moretta, Michael A. Caligiuri, E. Antonio Chiocca*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

154 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1827-1834
Number of pages8
JournalNature Medicine
Issue number12
StatePublished - Dec 2012

Bibliographical note

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.


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