Gene transfer of CD40-ligand to dendritic cells stimulates interferon-gamma production to induce growth arrest and apoptosis of tumor cells.

Abstract

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.

• Authors: K Tomihara, K Kato, Y Masuta, K Nakamura, H Uchida, K Sasaki, T Tanaka, J Huang, H Hiratsuka, H Hamada
• Journal: Gene therapy (Gene Ther) Vol. 15 Issue 3 Pg. 203-13 (Feb 2008) ISSN: 1476-5462 [Electronic] England
• PMID: 17989706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• CD40 Ligand
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Apoptosis
• CD40 Ligand (genetics, metabolism)
• Carcinoma, Squamous Cell (immunology, pathology, therapy)
• Cell Line, Tumor
• Dendritic Cells (metabolism)
• Gene Expression
• Genetic Therapy (methods)
• Humans
• Immunotherapy (methods)
• Interferon-gamma (immunology)
• Interleukin-12 (metabolism)
• Mice
• Mice, Nude
• Models, Animal
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Skin Neoplasms (immunology, pathology, therapy)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Transduction, Genetic (methods)
• Transplantation, Heterologous