The transcription factor C/EBPbêta orchestrates dendritic cell maturation and functionality under homeostatic and malignant conditions
Menée in vitro et à l'aide de modèles murins, cette étude analyse le rôle du facteur de transcription C/EBPbêta dans la maturation et la fonction immunogène des cellules dendritiques évoluant dans un environnement homéostatique ou modifié par des cellules de lymphome
Complex transcription factor networks regulate the development, maturation, and lineage commitment of dendritic cell (DC) subsets. Here, we demonstrate a previously unexpected role of the transcription factor C/EBPβ in murine DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Regulated expression of functional C/EBPβ isoforms enables a controlled maturation of DCs. In contrast, the presence of lymphoma cells leads to an up-regulation of C/EBPβ in DCs which transforms them into an immature and protumorigenic subtype. This study also shows that inhibition of the C/EBPβ/mTOR signaling axis abrogates the protumorigenic function of human DCs, suggesting that inhibitors regulating C/EBPβ activity can be used for blocking tumor-promoting functions of DCs in the treatment of hematological neoplasms.Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPβ in CD11c+MHCIIhi DCs, gene expression profiles of splenic C/EBPβ−/− DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c+MHCIIhiCD64+ DC compartment was also increased, suggesting that C/EBPβ deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPβ could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ−/− bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPβ plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis.Microarray data are available at the Gene Expression Omnibus database under accession number GSE123593. All other study data are included in the article and SI Appendix.