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Reciprocal Human Dendritic Cell–Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus¹

Robin J. Prestwich^2,*, Fiona Errington^2,*, Lynette P. Steele^*, Elizabeth J. Ilett^*, Ruth S. M. Morgan^*, Kevin J. Harrington, Hardev S. Pandha, Peter J. Selby^*, Richard G. Vile^*,,¶ and Alan A. Melcher^3,*

^* Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom; Institute of Cancer Research, Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London, United Kingdom; Postgraduate Medical School, University of Surrey, Guildford, United Kingdom; Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905; and ^¶ Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905

Oncolytic virotherapy may mediate antitumor effects via direct oncolysis or immune-mediated tumor regression. Although the ability of oncolytic viruses to generate adaptive antitumor immunity has been characterized, their interactions with the innate immune system are relatively unclear. Using a human in vitro system, this study investigates the innate immunological consequences of reovirus therapy and its potential to activate NK cell-mediated antitumor activity. Dendritic cells (DC) loaded with reovirus-infected human melanoma Mel888 cells (DC-MelReo), but not reovirus-infected tumor cells alone, induced IFN- production within the NK cell population upon coculture with PBMC, in a cell-to-cell contact-dependent manner. DC-MelReo secreted the chemokines CCL2, 3, 4, 5, 7, 8, 11, and CXCL10; these culture supernatants induced NK cell chemotaxis. Coculture of DC-MelReo with purified NK cells induced reciprocal contact-dependent phenotypic DC maturation, while DC-MelReo elicited up-regulation of the activation marker CD69 on NK cells, in a partially contact and partially IL-12 dependent manner. Significantly, DC-MelReo induced NK cell cytotoxicity toward tumor cells by a type I IFN dependent mechanism. These data demonstrate that tumor infection by reovirus can act via DC to induce NK cell recruitment, activation, and cytotoxicity, along with reciprocal DC maturation. These findings suggest that reciprocal DC-NK cell interactions, following reovirus therapy, may play an important role in altering the immune milieu of the tumor microenvironment and mediating tumor regression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ R.J.P., F.E., K.J.H., and A.A.M. are supported by grants from Cancer Research U.K., and R.V. by a National Institutes of Health Grant CA R01107032-02, Mayo Foundation, Richard M. Schulze Family Foundation. A.A.M., K.J.H., and R.V. have received research grants from Oncolytics Biotech.

² R.J.P. and F.E. contributed equally to this study.

³ Address correspondence and reprint requests to Prof. Alan Melcher, Level 5, Welcome Trust Brenner Building, St. James’s University Hospital, Beckett Street, Leeds, U.K. E-mail address: A.A.Melcher{at}leeds.ac.uk

⁴ Abbreviations used in this paper: DC, dendritic cell; DC-MelReo, reovirus loaded DC; PFA, paraformaldehyde.