title: Functional characterization of a STAT3-dependent dendritic cell-derived CD14+cell population arising upon IL-10-driven maturation.
abstract: Interleukin (IL)-10 is a major cancer-related immunosuppressive factor, exhibiting a unique ability to hamper the maturation of dendritic cells (DCs). We have previously reported that IL-10 induces the conversion of activated, migratory CD1a+DCs found in the human skin to CD14+CD141+macrophage-like cells. Here, as a model of tumor-conditioned DC maturation, we functionally assessed CD14-and CD14+DCs that matured in vitro upon exposure to IL-10. IL-10-induced CD14+DCs were phenotypically characterized by a low maturation state as well as by high levels of BDCA3 and DC-SIGN, and as such they closely resembled CD14+cells infiltrating melanoma metastases. Compared with DC matured under standard conditions, CD14+DCs were found to express high levels of B7-H1 on the cell surface, to secrete low levels of IL-12p70, to preferentially induce TH2 cells, to have a lower allogeneic TH cell and tumor antigen-specific CD8+T-cell priming capacity and to induce proliferative T-cell anergy. In contrast to their CD14+counterparts, CD14-monocyte-derived DCs retained allogeneic TH priming capacity but induced a functionally anergic state as they completely abolished the release of effector cytokines. Transcriptional and cytokine release profiling studies indicated a more profound angiogenic and pro-invasive signature of CD14+DCs as compared with DCs matured in standard conditions or CD14-DCs matured in the presence of IL-10. Importantly, signal transducer and activator of transcription 3 (STAT3) depletion by RNA interference prevented the development of the IL-10-associated CD14+phenotype, allowing for normal DC maturation and providing a potential means of therapeutic intervention.
authors.affiliation: Department of Medical Oncology; VU University Medical Center-Cancer Center; Amsterdam, The Netherlands.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Lindenberg
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.forename: Anoek
authors.initials: A
authors.lastname: Zomer
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Victor L
authors.initials: VL
authors.lastname: Thijssen
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
keywords: CD14; CD141/BDCA3; DC-SIGN; IL-10; dendritic cell; differentiation; monocyte; suppression; tumor microenvironment