Enhanced dendritic cell maturation by TNF-alpha or cytidine-phosphate-guanosine DNA drives T cell activation in vitro and therapeutic anti-tumor immune responses in vivo.
Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-alpha or a cytidine-phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-alpha had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.
Brunner
C
C
Divisions of. Clinical Pharmacology and Neuroendocrinology, Departments of Medicine and Radiation Therapy, Ludwig-Maximilians-University of Munich, Munich, Germany.
Seiderer
J
J
Schlamp
A
A
Bidlingmaier
M
M
Eigler
A
A
Haimerl
W
W
Lehr
H A
HA
Krieg
A M
AM
Hartmann
G
G
Endres
S
S
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology* / Q000627:therapeutic use; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018899:CpG Islands / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D006131:Growth Inhibitors / Q000276:immunology / Q000627:therapeutic use; D016219:Immunotherapy, Adoptive / Q000379:methods; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D006131:Growth Inhibitors; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4