Generation of potent anti-tumor immunity in mice by interleukin-12-secreting dendritic cells.
To induce cytolytic immunity, dendritic cells (DCs) need to release bioactive interleukin-12 (IL-12) p70 heterodimeric molecules. To study the role of IL-12 for the generation of an anti-tumor immune response, we generated two classes of DCs. (1) DCs were initiated to secrete IL-12 by exposure to LPS/IFN-gamma for 2 h resulting, as demonstrated in vitro, in continued IL-12 release for another 24 h (termed active DCs). (2) DCs were exposed to LPS/IFN-gamma for 24 h and injected into mice at a time point when IL-12 production had ceased (termed exhausted DCs). These two classes of DCs were probed for their capacity to induce a cytolytic anti-tumor immune response in vivo in a syngeneic mouse tumor model. The mouse tumor cell line K-Balb was engineered to express neomycin phosphotransferase (NPT) as a model tumor antigen. DCs were charged with various NPT-derived antigens, including recombinant NPT protein, whole tumor cell lysate and NPT-derived synthetic peptides, and the induction of in vivo anti-tumor immunity was determined by measuring tumor growth. Only the injection of active DCs, i.e., cells that maintained the capacity to secrete IL-12, but not exhausted DCs that had lost the ability to produce IL-12, resulted in a measurable deceleration of growth of K-Balb-NPT tumors. This anti-tumor immune response was most pronounced when using recombinant protein as an antigen source, which was evident in a prophylactic as well as in a therapeutic setting. The absence of a response to parental K-Balb tumors confirmed the antigen specificity of the anti-tumor immune response. Together these data provide evidence for the unique capacity of actively IL-12 secreting DCs to trigger effective anti-tumor immunity using exogenous tumor antigens.
Hüttner
Katharina Gabriele
KG
Children's Cancer Research Institute, St. Anna Children's Hospital, Kinderspitalgasse 6, 1090 Vienna, Austria.
Breuer
Sabine Konstanze
SK
Paul
Petra
P
Majdic
Otto
O
Heitger
Andreas
A
Felzmann
Thomas
T
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D000939:Epitopes; D015316:Genetic Therapy / Q000379:methods*; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism*; D019868:Kanamycin Kinase / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D021122:Protein Subunits / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D016827:CD8 Antigens; D000939:Epitopes; D008070:Lipopolysaccharides; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma; D019868:Kanamycin Kinase