期刊
ONCOIMMUNOLOGY
卷 2, 期 4, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/onci.23837
关键词
CD14; CD141; BDCA3; DC-SIGN; dendritic cell; differentiation; IL-10; monocyte; suppression; tumor microenvironment
资金
- Netherlands Organization for Scientific Research (NWO) [917-56-321]
- Dutch Cancer Society [UM2008-4101, VU2009-4358]
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.
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