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.

Dendritic Cell Plasticity in Tumor-Conditioned Skin: CD14+ Cells at the Cross-Roads of Immune Activation and Suppression

“…Consistent with these tolerogenic qualities, IL-10-induced CD14 + macrophage-like MoDCs expressed high levels of immune suppression-related transcripts such as Indoleamine 2,3-dioxygenase (IDO), IL-4Rα, IL-6R, TGFβ1, HIF1α, and VEGFA (17). Activation of a HIF1α transcriptional signature has been reported in tumor-associated macrophages, even under normoxic conditions (36).…”

CD14+macrophage-like cells as the linchpin of cervical cancer perpetrated immune suppression and early metastatic spread: A new therapeutic lead?

“…Indeed, we and others have previously shown that monocyte-to-DC differentiation can be diverted to the development of M2-like cells in the presence of primary tumor supernatants, mostly due to high levels of prostaglandin-E2 (PGE2) and interleukin (IL)-6. 4 In primary cervical tumors, CD14 C cells are present in large quantities 5 , and can actually adopt a T cell-stimulatory M1-phenotype, which, in conjunction with CD8 C T cell infiltration, resulted in a prognostically favorable association with overall survival. Additionally, these M2-like cells expressed proangiogenic and pro-tumor invasive factors ( Fig.…”

“…4 In primary cervical tumors, CD14 C cells are present in large quantities 5 , and can actually adopt a T cell-stimulatory M1-phenotype, which, in conjunction with CD8 C T cell infiltration, resulted in a prognostically favorable association with overall survival. 4 In cervical TDLN, we also found a clear and significant correlation between frequencies of Tregs and rates of CD14 C M2-like cells as well as their expression levels of PD-L1. 1 This is proof of early immune suppression in TDLN preceding actual metastatic spread and indicates the importance for tumor invasion of sabotaging effector T cells.…”

“…1 Aberrant myeloid differentiation has been linked to JAK2/ STAT3 signaling. 1,2,4,6 Ideally, a combinatorial immunotherapy should be pursued by blocking immune suppression (e.g., through blockade of PD-L1 or STAT3/ p38 signaling), thereby minimizing the negative impact of CD14 C M2-macrophage-like cells, while promoting an antitumor response in the TDLN, e.g., by immune potentiation or vaccination. 6 Another approach is to block upstream-acting IL-6 or cyclooxygenase (COX) ¡1/¡2 (i.e., the catalytic enzymes controlling PGE2 production), 2,3,7 possibly in combination with conventional chemotherapy.…”

The Sca1+ mesenchymal stromal subpopulation promotesdendritic cell commitment in the niche

“…The hematopoietic-specific deletion of the STAT3 gene results in an acute loss of conventional dendritic cells (cDCs) and attenuated responses to the Fms-related tyrosine kinase 3 ligand (Flt3L) in vivo (Laouar et al, 2003). The STAT3 signal enhanced CD14 + DC development (Lindenberg et al, 2013). Conversely, overexpression of STAT3 promoted DC maturation from hematopoietic progenitors (Onai et al, 2006).…”