CD40ligand‐expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo

• Published in: Hepatology (Baltimore, Md.) Vol. 48; no. 1; pp. 157 - 168
• Main Authors: Gonzalez‐Carmona, Maria A., Lukacs‐Kornek, Veronika, Timmerman, Anne, Shabani, Sara, Kornek, Miroslaw, Vogt, Annabelle, Yildiz, Yildiz, Sievers, Elisabeth, Schmidt‐Wolf, Ingo G.H., Caselmann, Wolfgang H., Sauerbruch, Tilman, Schmitz, Volker
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2008; Wiley
• Subjects: Animals; Biological and medical sciences; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - surgery; CD40 Ligand - metabolism; Cell Line, Tumor; Coculture Techniques; Cytotoxicity, Immunologic; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - transplantation; Disease Progression; Gastroenterology. Liver. Pancreas. Abdomen; Immunity, Active; Immunity, Innate; Injections, Intralesional; Interleukin-12 - blood; Interleukin-12 - metabolism; Liver Neoplasms, Experimental - immunology; Liver Neoplasms, Experimental - pathology; Liver Neoplasms, Experimental - surgery; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocytes - immunology; Male; Medical sciences; Mice; Mice, Inbred C3H; Neoplasm Recurrence, Local - prevention & control; Phenotype; Spleen - cytology; Transduction, Genetic; Tumors; Vaccination; Dendritic cell; In vivo; Gastroenterology; Digestive diseases; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Immunity; Cancer
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.22296

Dendritic cells (DCs) are professional antigen‐presenting cells able to prime T‐cells against tumor‐associated antigens (TAA), but their potential to induce hepatocellular carcinoma (HCC) regression is still limited. CD40/CD40L interaction is essential for DC activation and induction of antigen‐specific T‐cells. In this study, transduction of TAA‐pulsed DC with a CD40L‐encoding adenovirus (Ad‐CD40L) was used to improve the immune response induced by DC toward HCC. Bone marrow–derived DC from C3H/HeNcrl mice were cultured with granulocyte‐macrophage colony‐stimulating factor and interleukin‐4. On day 6, tumor‐lysate pulsed DCs were infected with adenoviruses. HCCs were induced by inoculation of mice with Hepa129‐cells subcutaneously. When tumor‐volume was 100 to 400 mm3, DCs were injected intratumorally, subcutaneously, or intravenously. Ad‐CD40L transduction exerted CD40/CD40L interactions between DCs, increasing DC immunostimulation with up‐regulation of CD80/CD86‐ and interleukin‐12 (IL‐12) expression. Intratumoral injection of CD40L‐DC was superior to intravenous or subcutaneous treatments, yielding tumor elimination in almost 70% of mice. Moreover, all tumor‐free animals were protected against hepatic tumor cell rechallenge. In a preventive setting, subcutaneous injection of CD40L‐expressing DCs protected 50% of mice for more than 3 months toward tumor cell challenge. The induced immune response seemed to be dependent on cross‐priming with Th1‐lymphocytes in the lymph nodes, because transduced DCs were redetected in lymphoid tissues. In addition, immunohistochemistry of tumors indicated a significant tumor infiltration with CD4+, CD8+ T cells and natural killer (NK) cells. Tumor‐infiltrating lymphocytes were tumor‐specific, as shown in interferon‐gamma (IFN‐γ) enzyme‐linked immunosorbent spot and T‐cell proliferation assays. Conclusion: Transduction of DCs with Ad‐CD40L increases significantly the stimulatory capacity of DCs. Intratumoral injection of DCs activates both acquired and innate immunity, inducing complete regression of established tumors and long‐term immunity against tumor recurrence. This approach improves the antitumoral potential of DCs. (HEPATOLOGY 2008.)