Abstract 1514: Oncolytic viral therapy for glioblastoma induces robust natural killer cell activation

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Abstract Oncolytic viral (OV) therapy is a promising treatment being tested for safety and efficacy. Natural killer cells (NK) limit viral infections, and previous work suggests they may similarly attenuate virotherapy. We used flow cytometry to evaluate the temporal pattern of NK recruitment in intracranial tumors (U87DEGFR glioma) treated with the oncolytic herpes virus, rQnestin 34.5, or PBS. Quantification of NK recruitment into intracranial tumors treated with rQnestin34.5 or PBS revealed significant enrichment of these cells into the tumor hemisphere at early timepoints and continuing through 72 hours (2.2-fold, p=0.02) following infection. Moreover, NK cells recruited to the site of inoculation exhibited an activated phenotype, including enhanced CD69, CD62L, CD27, NKG2D, and CD127 staining compared to PBS treated mice. This robust NK response was demonstrated to be detrimental to OV efficacy through the enhanced survival of NK depleted mice treated with OV compared to OV treated mice containing NK cells (median survival 31.6 days compared to median survival 23.6 days, p=0.04). Since NK cells are recruited into the tumor microenvironment following infection, we postulated that OV infection of glioma cells was also activating NK cells. We measured granzyme B and IFNg production by NK cells in the presence of infected or uninfected glioma. Our results indicate that glioma mediated activation of NK cells was augmented by OV infection. Additionally, these findings were corroborated with increased NK killing of OV infected glioma compared to uninfected glioma. Due to the enhanced NK cytotoxic properties induced by OV infection, we proceeded to investigate the expression of NK activating ligands on the surface of infected glioma cells that could potentially mediate this effect. Focusing on ligands for NKG2D and the natural cytotoxicity receptors (NKp30, NKp44, and NKp46), viral infection of cultured gliomas was shown to upregulate ligand expression for NKG2D (24%, p=0.004), NKp46 (41%, p=0.01), and NKp30 (2.75-fold, p=0.001) while selectively downregulating ligand expression for NKp44 (2.8-fold, p=0.005). These findings suggest that viral infection of gliomas is altering the ligand signature for NK activation. Since NK cells possess both antiviral and antitumor properties, further work will investigate if virus induced NK activating signals can be selectively blocked in order to enhance viral efficacy while maintaining NK antitumor efficacy. This is the first study investigating the changes in NK cell activation and recruitment in gliomas upon oncolytic HSV-1 treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1514.