Reovirus activates human dendritic cells to promote innate antitumor immunity.
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-kappaB 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.
Errington
Fiona
F
Cancer Research U.K., St. James's University Hospital, Beckett Street, Leeds.
Steele
Lynette
L
Prestwich
Robin
R
Harrington
Kevin J
KJ
Pandha
Hardev S
HS
Vidal
Laura
L
de Bono
Johann
J
Selby
Peter
P
Coffey
Matt
M
Vile
Richard
R
Melcher
Alan
A
D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D012089:Mammalian orthoreovirus 3 / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014779:Virus Replication / Q000276:immunology
D016207:Cytokines; D016328:NF-kappa B