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The Journal of Immunology, 2008, 180, 6018 -6026
Copyright © 2008 by The American Association of Immunologists, Inc.

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*Substance via MeSH
Medline Plus Health Information
*Cancer

Reovirus Activates Human Dendritic Cells to Promote Innate Antitumor Immunity1

Fiona Errington*, Lynette Steele*, Robin Prestwich*, Kevin J. Harrington2,{dagger},{ddagger}, Hardev S. Pandha§, Laura Vidal{dagger}, Johann de Bono, Peter Selby*, Matt Coffey||, Richard Vile# and Alan Melcher2,*

* Cancer Research U.K., St. James’s University Hospital, Leeds; {dagger} Targeted Therapy Laboratory, Institute of Cancer Research, Cancer Research U.K. Centre for Cell and Molecular Biology, Chester Beatty Laboratories; {ddagger} Head and Neck Unit, Royal Marsden Hospital, London; § Universtiy of Surrey, Guilford; Drug Development Unit, Royal Marsden Hospital, Sutton, United Kingdom; || Oncolytics Biotech, Calgary, Canada; and # Molecular Medicine Program, Mayo Clinic, Rochester, MN 55905

Oncolytic viruses can exert their antitumor activity via direct oncolysis or activation of antitumor immunity. Although reovirus is currently under clinical investigation for the treatment of localized or disseminated cancer, any potential immune contribution to its efficacy has not been addressed. This is the first study to investigate the ability of reovirus to activate human dendritic cells (DC), key regulators of both innate and adaptive immune responses. Reovirus induced DC maturation and stimulated the production of the proinflammatory cytokines IFN-{alpha}, TNF-{alpha}, IL-12p70, and IL-6. Activation of DC by reovirus was not dependent on viral replication, while cytokine production (but not phenotypic maturation) was inhibited by blockade of PKR and NF-{kappa}B signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-{gamma} production and increased NK cytolytic activity. Moreover, short-term coculture of reovirus-activated DC with autologous T cells also enhanced T cell cytokine secretion (IL-2 and IFN-{gamma}) and induced non-Ag restricted tumor cell killing. These data demonstrate for the first time that reovirus directly activates human DC and that reovirus-activated DC stimulate innate killing by not only NK cells, but also T cells, suggesting a novel potential role for T cells in oncolytic virus-induced local tumor cell death. Hence reovirus recognition by DC may trigger innate effector mechanisms to complement the virus’s direct cytotoxicity, potentially enhancing the efficacy of reovirus as a therapeutic agent.

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 This work was supported by Cancer Research U.K. and Oncolytics Biotech.

2 Address correspondence and reprint requests to Dr. Alan Melcher, Cancer Research U.K., St. James’s University Hospital, Beckett Street, Leeds, LS9 7TF, U.K. E-mail address: alan.melcher{at}cancer.org.uk

3 Abbreviations used in this paper: PKR, protein kinase receptor; TAA, tumor-associated Ag; PRR, pattern recognition receptor; DC, dendritic cell; reo-DC, reovirus-activated DC; iDC, immature DC; 2-AP, 2-aminopurine; Treg, regulatory T cell; CAPE, caffeic acid phenethyl ester.




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