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OK432-Activated Human Dendritic Cells Kill Tumor Cells via CD40/CD40 Ligand Interactions¹

Katy S. Hill^2,*, Fiona Errington^2,*, Lynette P. Steele^*, Alison Merrick^*, Ruth Morgan^*, Peter J. Selby^*, Nikolaos T. Georgopoulos^3,, Dearbhaile M. O'Donnell^3, and Alan A. Melcher^3,4,*

^* Cancer Research U.K., St. James’s University Hospital, Leeds, and Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University of York, York, U.K.; and Academic Unit of Medical and Clinical Oncology, St. James’s Hospital, Dublin, Ireland

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- 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.

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.

² K.S.H. and F.E. contributed equally to the manuscript.

³ N.T.G., A.A.M., and D.M.O. are joint senior authors.

⁴ 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

⁵ Abbreviations used in this paper: DC, dendritic cell; OK-DC, DC matured with OK432; LPS/IFN-DC, DC matured with lipopolysaccharide and IFN-; IDC, immature DC; HFF, human foreskin fibroblast; NHU, normal human urothelial; TRAF, TNFR-associated factor.