title: Dendritic cell maturation with poly(I:C)-based versus PGE2-based cytokine combinations results in differential functional characteristics relevant to clinical application.
abstract: 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.
authors.affiliation: Department of Hematology/Oncology, University of Freiburg Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Möller
authors.forename: Kathrin
authors.initials: K
authors.lastname: Michel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Frech
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.forename: Hendrik
authors.initials: H
authors.lastname: Veelken
authors.forename: Anna-K
authors.initials: AK
authors.lastname: Thomas-Kaskel
mesh_terms: 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
chemical_list: D016207:Cytokines; C531098:HNA-4A antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007519:Isoantigens; D015232:Dinoprostone; D011070:Poly I-C