Gene transfer of CD40-ligand to dendritic cells stimulates interferon-gamma production to induce growth arrest and apoptosis of tumor cells.
In this study, we present evidence that gene transfer of the CD40-ligand (CD154) into human immature dendritic cells (DC) imparts direct antitumor effects on tumor cells. DC infected with adenovirus directed to express human CD154 on the cell surface (CD154-DC) elicited significantly higher levels of immune accessory molecules commonly found on mature DC. We found that co-cultivation with a human squamous cell carcinoma cell line (OSC-70) with CD154-DC significantly inhibited cell growth. We further demonstrate that OSC-70 cells stimulated with CD154-DC were more susceptible to apoptosis via TNF-related apoptosis inducing ligand (TRAIL). Importantly, tumor cells co-cultured with CD154-DC in transwell plates expressed upregulated cell surface TRAIL-R2. CD154-DC produced higher levels of interferon (IFN)-gamma, IL-12p70 and soluble CD154, but the ability of CD154-DC to inhibit tumor cell growth was significantly abrogated by a neutralizing antibody to IFN-gamma, indicating that this was mainly mediated by IFN-gamma. Furthermore, intratumoral injection of CD154-DC significantly suppressed OSC-70 tumor growth in a xenograft model. Overall, these results reveal that CD154-DC have potential as an anti-cancer therapy by producing IFN-gamma to arrest adjacent tumor cell growth and increase the susceptibility of apoptosis via TRAIL.
Tomihara
K
K
Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan.
Kato
K
K
Masuta
Y
Y
Nakamura
K
K
Uchida
H
H
Sasaki
K
K
Tanaka
T
T
Huang
J
J
Hiratsuka
H
H
Hamada
H
H
D000818:Animals; D017209:Apoptosis; D023201:CD40 Ligand / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D014183:Transplantation, Heterologous
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma