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

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Abstract

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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Figure 1: oHSV administration induces NK cell recruitment to the tumor-bearing brain.
Figure 2: NK cells are activated after oHSV therapy.
Figure 3: NK cells mediate macrophage and microglia activation after oHSV therapy.
Figure 4: NK cell depletion enhances oHSV efficacy.
Figure 5: IL-15–stimulated NK cells preferentially lyse oHSV-infected human and mouse glioblastoma.
Figure 6: NKp30 and NKp46 orchestrate NK cell–mediated killing of oHSV-infected glioblastoma cells in vitro, and NKp46 mediates viral clearance in vivo.

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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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Acknowledgements

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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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.

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Correspondence to Michael A Caligiuri or E Antonio Chiocca.

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Alvarez-Breckenridge, C., Yu, J., Price, R. et al. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nat Med 18, 1827–1834 (2012). https://doi.org/10.1038/nm.3013

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