Dendritic cell maturation with poly(I:C)-based versus PGE2-based cytokine combinations results in differential functional characteristics relevant to clinical application.
In vitro maturation of dendritic cells (DCs) for cancer immunotherapy may be accomplished by cytokine cocktails containing prostaglandin E2 (PGE2). More recently, a poly(I:C)-based protocol has been proposed as a potentially superior alternative because of a strong induction of interleukin (IL)-12 secretion by resulting DCs. As optimal DC maturation represents a crucial issue for cancer vaccination trials, we performed a systematic and comprehensive comparison of both protocols with respect to important indicators of DC function. Although both methods yielded phenotypically mature DCs, transcriptional profiling revealed a substantially higher number of differentially regulated genes after poly(I:C)-based than PGE2-based maturation. Several of these are involved in immunologic processes, indicating that both DC types exhibit subtle, but distinct, molecular properties. Up-regulation of genes encoding the T-cell-attracting chemokines CXCL9, 10, and 11 in poly(I:C)-DC but not PGE2-DC was confirmed on a protein level. Although poly(I:C)-based maturation induced substantial IL-12p70 secretion, poly(I:C)-DC also secreted low levels of IL-10 and showed a significantly higher expression of functionally active indoleamine-2,3-dioxygenase than PGE2-DC, which might mediate immune inhibitory functions. Nonetheless, the number of peptide-specific T cells tended to be higher after in vitro priming with poly(I:C)-DC compared with PGE2-DC. Finally, PGE2-DC displayed superior migratory abilities, which are essential for in vivo applications. In summary, we have identified previously unrecognized shared and distinct molecular features of DCs matured by 2 commonly used protocols that lead to subtle, but significant, immunologic features of the resulting cells relevant to clinical applications.
Möller
Ines
I
Department of Hematology/Oncology, University of Freiburg Medical Center, University of Freiburg, Freiburg, Germany.
Michel
Kathrin
K
Frech
Nathalie
N
Burger
Meike
M
Pfeifer
Dietmar
D
Frommolt
Peter
P
Veelken
Hendrik
H
Thomas-Kaskel
Anna-K
AK
D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; C531098:HNA-4A antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007519:Isoantigens; D015232:Dinoprostone; D011070:Poly I-C