OK432-activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions

Katy S. Hill, Fiona Errington, Lynette P. Steele, Alison Merrick, Ruth Morgan, Peter J. Selby, Nikolaos T. Georgopoulos, Dearbhaile M. O'Donnell, Alan A. Melcher

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20 Citations (Scopus)

Abstract

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-γ secretion, expressed CCR7, and migrated in response to MIP-3β. 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.

Original languageEnglish
Pages (from-to)3108-3115
Number of pages8
JournalJournal of Immunology
Volume181
Issue number5
DOIs
Publication statusPublished - 1 Sep 2008
Externally publishedYes

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    Hill, K. S., Errington, F., Steele, L. P., Merrick, A., Morgan, R., Selby, P. J., ... Melcher, A. A. (2008). OK432-activated human dendritic cells kill tumor cells via CD40/CD40 ligand interactions. Journal of Immunology, 181(5), 3108-3115. https://doi.org/10.4049/jimmunol.181.5.3108