RRC ID 45547
Author Tomihara K, Kato K, Masuta Y, Nakamura K, Tanaka T, Hiratsuka H, Hamada H.
Title Gene transfer of the CD40-ligand to human dendritic cells induces NK-mediated antitumor effects against human carcinoma cells.
Journal Int J Cancer
Abstract The CD40-ligand (CD40L) is a key molecule for the activation of dendritic cells (DCs), followed by the induction of DC maturation and cytokine production. Here we found that DC infected with adenovirus vector encoding human CD40L (CD40L-DC) displayed significantly higher levels of immune accessory molecules and IL-12 production than did uninfected cells, and that CD40L-DC produced much higher levels of IFN-gamma. To investigate whether CD40L-DC-derived these soluble factors could stimulate NK cells without physical cell-to-cell contact, we cocultured NK cells with CD40L-DC in transwell culture plates. NK cells showed up-regulated cytotoxic activity toward various squamous oral cell carcinoma (OSC-70, HSC-2, HSC-3), and we determined that both IL-12 and IFN-gamma contributed to the CD40L-DC-mediated NK cell activation. NK cells stimulated with CD40L-DC resulted in the induction of the cell surface expression of TRAIL, the production of IFN-gamma and intracellular accumulation of granzyme B. The cytotoxic activity of NK cells stimulated with CD40L-DC could be mostly inhibited by neutralizing antibody for TRAIL and completely abrogated by the combination of antibody and exocytosis inhibitor, indicating that this was mainly mediated by a TRAIL-TRAIL-receptor interaction and granule exocytosis. Moreover, CD40L-DC-activated NK cells could induce up-regulation of a death-receptor TRAIL-R2 (DR5) and down-regulation of a decoy receptor TRAIL-R3 (DcR1) on carcinoma cells. Overall, these results have revealed that CD40L-DC could activate an innate immune reaction by stimulating NK cells followed by carcinoma cells, supporting that administration of CD40L-DC may have potential as an anticancer therapy.
Volume 120(7)
Pages 1491-8
Published 2007-4-1
DOI 10.1002/ijc.22518
PMID 17205529
MeSH Adenoviridae / genetics CD40 Ligand / genetics CD40 Ligand / pharmacology* Carcinoma, Squamous Cell / immunology Carcinoma, Squamous Cell / secondary Carcinoma, Squamous Cell / therapy* Cytotoxicity, Immunologic Dendritic Cells / cytology Dendritic Cells / immunology* Dendritic Cells / metabolism Gene Transfer Techniques* Genetic Therapy Humans Interferon-gamma / metabolism Interleukin-12 / metabolism Killer Cells, Natural / immunology* Lymphocyte Activation Mouth Neoplasms / immunology Mouth Neoplasms / metabolism Mouth Neoplasms / therapy* Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism T-Lymphocytes, Cytotoxic TNF-Related Apoptosis-Inducing Ligand / metabolism Transfection Tumor Cells, Cultured / immunology Tumor Cells, Cultured / metabolism Tumor Cells, Cultured / pathology
IF 5.145
Times Cited 15
DNA material pCAhCD40L (RDB03915) pWEAxCAhCD40L-FRGD (RDB03916) AxCAhCD40L-FRGD (RDB03917).