Functional characterization of a STAT3-dependent dendritic cell-derived CD14⁺ cell population arising upon...

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.