title: Plasmacytoid dendritic cell-derived IFN-alpha induces TNF-related apoptosis-inducing ligand/Apo-2L-mediated antitumor activity by human monocytes following CpG oligodeoxynucleotide stimulation.
abstract: Immunostimulatory oligodeoxynucleotides (ODN) containing the CpG motif are being tested as immune adjuvants in many disease settings. Of the human PBMC examined, plasmacytoid dendritic cells (pDC) are a major source of type I IFN upon stimulation with CpG ODN. IFNs have numerous immunostimulatory effects, including the induction of TNF-related apoptosis-inducing ligand (TRAIL)/Apo-2L on monocytes, NK cells, and T cells. Importantly, IFN has also been linked to antitumor responses. Thus, we tested whether CpG ODN stimulation of PBMC led to TRAIL/Apo-2L-induced tumor cell death. When PBMC were stimulated with CpG ODN, TRAIL/Apo-2L-dependent tumor cell death was observed. Further examination of CpG ODN-stimulated PBMC revealed that TRAIL/Apo-2L expression was limited to CD14(+) cells, which, when depleted, led to a loss of the TRAIL/Apo-2L-mediated tumor cell killing. Moreover, pDC depletion also abolished the TRAIL/Apo-2L-mediated killing of tumor cell targets. Analysis of the pDC showed IFN-alpha production after CpG ODN stimulation. Finally, inclusion of neutralizing IFN-alpha antiserum with the PBMC during CpG ODN stimulation abrogated TRAIL/Apo-2L-mediated tumor cell killing. These results define a mechanism by which CpG ODN induces TRAIL/Apo-2L-dependent killing of tumor cells by CD14(+) PBMC, in which CpG ODN-activated pDC produce IFN-alpha that stimulates CD14(+) PBMC to express functional TRAIL/Apo-2L.
authors.affiliation: Department of Urology, Interdisciplinary Graduate Program in Immunology, and Prostate Cancer Research Program of Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Troy J
authors.initials: TJ
authors.lastname: Kemp
authors.forename: Bennett D
authors.initials: BD
authors.lastname: Elzey
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood* / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010950:Plasma Cells / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C408982:CPG-oligonucleotide; D016898:Interferon-alpha; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha