Reovirus activates human dendritic cells to promote innate antitumor immunity

Fiona Errington, Lynette Steele, Robin Prestwich, Kevin J. Harrington, Hardev S. Pandha, Laura Vidal, Johann De Bono, Peter Selby, Matt Coffey, Richard Vile, Alan Melcher

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

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-α, TNF-α, 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-κB signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-γ 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-γ) 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.

Original languageEnglish (US)
Pages (from-to)6018-6026
Number of pages9
JournalJournal of Immunology
Volume180
Issue number9
DOIs
StatePublished - May 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Errington, F., Steele, L., Prestwich, R., Harrington, K. J., Pandha, H. S., Vidal, L., De Bono, J., Selby, P., Coffey, M., Vile, R., & Melcher, A. (2008). Reovirus activates human dendritic cells to promote innate antitumor immunity. Journal of Immunology, 180(9), 6018-6026. https://doi.org/10.4049/jimmunol.180.9.6018