OK432-activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions.
In vivo, dendritic cells (DC) are programmed to orchestrate innate and adaptive immunity in response to pathogen-derived "danger" signals. Under particular circumstances, DC can also be directly cytotoxic against tumor cells, potentially allowing them to release tumor associated Ags from dying cells and then prime antitumor immunity against them. In this study, we describe the innate characteristics of DC (OK-DC) generated in vitro after exposure of immature human myeloid-derived DC to OK432, a penicillin-inactivated and lyophilized preparation of Streptococcus pyrogenes. OK-DC produced proinflammatory cytokines, stimulated autologous T cell proliferation and IFN-gamma secretion, expressed CCR7, and migrated in response to MIP-3beta. Moreover, OK-DC displayed strong, specific cytotoxicity toward tumor cell targets. This cytotoxicity was associated with novel, OK432-induced up-regulation of CD40L on the cell surface of OK-DC, and was absolutely dependent on expression of CD40 on the tumor targets. These data demonstrate that maturation of human DC with OK432, an adjuvant suitable for clinical use, induces direct tumor cell killing by DC, and describes a novel CD40/CD40L-mediated mechanism for specific DC antitumor cytotoxicity.
Hill
Katy S
KS
Cancer Research U.K., St. James's University Hospital, Leeds, UK.
Errington
Fiona
F
Steele
Lynette P
LP
Merrick
Alison
A
Morgan
Ruth
R
Selby
Peter J
PJ
Georgopoulos
Nikolaos T
NT
O'Donnell
Dearbhaile M
DM
Melcher
Alan A
AA
D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010844:Picibanil / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D019013:CD40 Antigens; D023201:CD40 Ligand; D010844:Picibanil