CD40 ligation during dendritic cell maturation reduces cell death and prevents interleukin-10-induced regression to macrophage-like monocytes.
Dendritic cells (DCs) have become popular candidates in cancer vaccination because of their crucial role in inducing T-cell responses. However, clinical studies greatly differ in their protocols for generating DCs and the efficacy in treating established tumors needs to be improved. We systematically analyzed DCs maturated by five different protocols for surface markers, the alloproliferative T-cell response, the DC survival after cytokine deprivation, the stability of surface markers under the influence of interleukin-10 (IL-10) and the DC cytokine secretion pattern. Monocyte-derived DCs were maturated by CD40-ligand (CD40-L), unmethylated cytosine-guanosine dinucleotides-oligodinucleotides (CpG-ODN), an inflammatory cytokine cocktail (ICC), a combination of ICC and CD40-L, or ICC, CD40-L and CpG-ODN. A high co-expression of DC maturation and costimulation markers was found after treatment with ICC plus CD40-L (69.3 +/- 9.6% CD83/CD80 double positive staining) and correlated with a significantly increased cell survival, a high expression of the antiapoptotic factor bcl-(XL), a stable CD83(high)/CD14(low) expression under the influence of IL-10, and a strong alloproliferative T-cell response. In conclusion, our data support the use of maturation protocols containing ICC plus CD40-L in order to generate highly mature, phenotypically stable, cell-death resistant, and T-cell stimulatory DCs for clinical application in cancer patients.
Haenssle
Holger
H
Department of Dermatology, Georg-August-University Goettingen, Goettingen, Germany. h.haenssle@med.uni-goettingen.de
Buhl
Timo
T
Knudsen
Susanne
S
Krueger
Ullrich
U
Rosenberger
Albert
A
Reich
Kristian
K
Neumann
Christine
C
D015703:Antigens, CD / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods*; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007937:Leukapheresis; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D015703:Antigens, CD; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016753:Interleukin-10; D023201:CD40 Ligand