title: Improving immunotherapy of hepatocellular carcinoma (HCC) using dendritic cells (DC) engineered to express IL-12 in vivo.
abstract: BACKGROUND
  Interleukin 12 (IL-12), one of the most potent Th1-cytokines, has been used to improve dendritic cells (DC)-based immunotherapy of cancer. However, it failed to achieve clinical response in patients with hepatocellular carcinoma (HCC). In this study, improved conditions of immunotherapy with DC engineered to express IL-12 were studied in murine subcutaneous HCC.
  
  
  METHODS
  Tumour-lysate pulsed DC were transduced with IL-12-encoding adenoviruses or cultivated with recombinant (r)IL-12. DC were injected intratumourally, subcutaneously or intravenously at different stages of tumour-development.
  
  
  RESULTS
  Dendritic cell overexpressing IL-12 by adenoviruses showed enhanced expression of costimulatory molecules and stronger priming of HCC-specific effector cells than DC cultured with rIL-12. Intratumoural but not systemic injections of IL-12-DC induced the strongest antitumoural effects reaching complete regressions in 75% of early-staged tumours and in 33% of advanced tumours. Importantly, antitumoural effects could be further enhanced through combination with sorafenib. Analysing the tumour-environment, IL-12-DC increased the levels of Th1-cytokines/chemokines and of CD4(+) -, CD8(+) -T- and NK-cells. Induced immunity was tumour-specific and sustained since all tumour-free animals were protected towards hepatic tumour-cell rechallenge. However, IL-12-DC also enhanced immunosuppressive cytokines, regulatory T cells and even myeloid-derived suppressor cells within the tumours.
  
  
  CONCLUSIONS
  Induced IL-12-overexpression by adenoviral vectors can effectively immunostimulate DC. Intratumoural but not systemic injection of activated IL-12-DC was crucial for effective tumour regression. The mechanism of this approach seems to be the induction of a sufficient Th1 tumour-environment allowing the recruitment of effector cells rather than the inhibition of tumour immunosuppression. Thus, improved immunotherapy with IL-12-DC represents a promising approach towards HCC.
authors.affiliation: Department of Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Vogt
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sievers
authors.forename: Veronika
authors.initials: V
authors.lastname: Lukacs-Kornek
authors.forename: Georges
authors.initials: G
authors.lastname: Decker
authors.forename: Esther
authors.initials: E
authors.lastname: Raskopf
authors.forename: Nadja
authors.initials: N
authors.lastname: Meumann
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: Maria A
authors.initials: MA
authors.lastname: Gonzalez-Carmona
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics*; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D010671:Phenylurea Compounds; D018664:Interleukin-12; D009536:Niacinamide; D000077157:Sorafenib
keywords: IL-12; dendritic cells; hepatocellular carcinoma; immunosuppressive tumour-environment; immunotherapy