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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.

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  • 07 October 2013

     In the version of this article initially published, the Online Methods incorrectly stated that mouse NK cells were treated with a blocking antibody to mouse NKp46 called BAB281. The correct antibody used to treat the cells was 29A1.4. The error has been corrected in the HTML and PDF versions of the article.


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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.

Author information

Author notes

    • Christopher A Alvarez-Breckenridge
    •  & Jianhua Yu

    These authors contributed equally to this work.


  1. Medical Scientist Training Program, Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

    • Christopher A Alvarez-Breckenridge
    •  & Richard Price
  2. Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

    • Christopher A Alvarez-Breckenridge
    • , Richard Price
    • , Jeffrey Wojton
    • , Jason Pradarelli
    • , Yan Wang
    • , Jayson Hardcastle
    • , Balveen Kaur
    • , Sean E Lawler
    •  & E Antonio Chiocca
  3. Division of Hematology, Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

    • Jianhua Yu
    •  & Michael A Caligiuri
  4. Comprehensive Cancer Center, Ohio State University, Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

    • Jianhua Yu
    • , Hsiaoyin Mao
    • , Min Wei
    • , Shun He
    • , Soledad A Fernandez
    • , Balveen Kaur
    • , Michael A Caligiuri
    •  & E Antonio Chiocca
  5. Center for Biostatistics, Ohio State University Medical Center and James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA.

    • Soledad A Fernandez
  6. Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, INSERM, U631, Marseille, France.

    • Eric Vivier
  7. The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

    • Ofer Mandelboim
  8. Dipartimento di Medicina Sperimentale e Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy.

    • Alessandro Moretta
  9. Department of Neurosurgery, Brigham and Women's Hospital/Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts, USA.

    • E Antonio Chiocca


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C.A.A.-B., J.Y., R.P., J.W., J.P., H.M., M.W., Y.W., S.H. and J.H. performed experiments. C.A.A.-B., J.Y., B.K., S.E.L., A.M., M.A.C. and E.A.C. conceived the experimental approach, directed experiments and interpreted data. S.A.F. performed statistical analysis. E.V., O.M. and A.M. provided reagents. C.A.A.-B., J.Y., M.A.C. and E.A.C. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael A Caligiuri or E Antonio Chiocca.

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