Naturally produced type I IFNs enhance human myeloid dendritic cell maturation and IL-12p70 production and mediate elevated effector functions in innate and adaptive immune cells

Abstract

There has recently been a paradigm shift in the field of dendritic cell (DC)-based immunotherapy, where several clinical studies have confirmed the feasibility and advantageousness of using directly isolated human blood-derived DCs over in vitro differentiated subsets. There are two major DC subsets found in blood; plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), and both have been tested clinically. CD1c+ mDCs are highly efficient antigen-presenting cells that have the ability to secrete IL-12p70, while pDCs are professional IFN-α-secreting cells that are shown to induce innate immune responses in melanoma patients. Hence, combining mDCs and pDCs poses as an attractive, multi-functional vaccine approach. However, type I IFNs have been reported to inhibit IL-12p70 production and mDC-induced T-cell activation. In this study, we investigate the effect of IFN-α on mDC maturation and function. We demonstrate that both recombinant IFN-α and activated pDCs strongly enhance mDC maturation and increase IL-12p70 production. Co-cultured mDCs and pDCs additionally have beneficial effect on NK and NKT-cell activation and also enhances IFN-γ production by allogeneic T cells. In contrast, the presence of type I IFNs reduces the proliferative T-cell response. The mere presence of a small fraction of activated pDCs is sufficient for these effects and the required ratio between the subsets is non-stringent. Taken together, these results support the usage of mDCs and pDCs combined into one immunotherapeutic vaccine with broad immunostimulatory features.Electronic supplementary materialThe online version of this article (10.1007/s00262-018-2204-2) contains supplementary material, which is available to authorized users.

Sijunzi Tang and gefitinib cooperate to inhibit Lung cancer progression by modulating the pre-metastatic niche

“…Therefore, the increased expression levels of IL-23 and RANTES might be associated with the formation of pre-metastatic niche and SJZ could inhibit it. IL-12p70, as well as IL-15, was a common immune promoting factors [40,41] while IL-1α, IL-1β IL-18 and GRO-α were important cytokines involved in in ammatory processes which are considered as the facilitators in cancer metastasis [42][43][44][45] . We found that there were signi cant rises in the expression level of IL-12p70 and IL-15 while declines in the expression level of IL-1β IL-18 GRO-α in co-treatment group.…”

Type I and II Interferons in the Anti-Tumor Immune Response

“…In pre-clinical breast cancer models, restoration of IFNI activity in the TME via administration of TLR agonists increases activation of DCs and reduces mammary tumor growth [ 56 ]. As research into DC-based treatments has continued, IFNα exposure has been identified as an important step to allow vigorous immune responses following treatment and to improve efficacy of anti-tumor vaccines [ 57 , 58 , 59 , 60 ]. Finally, several clinical trials are currently underway to study the outcomes of STING agonists alone or in combination therapies [ 61 ].…”

IFN-Alpha-Mediated Differentiation of Dendritic Cells for Cancer Immunotherapy: Advances and Perspectives

“…IFN-α and IFN-β differently modulate DC activation/maturation, depending on the experimental model and culture conditions. Indeed, IFN-α has been shown to markedly enhance DC maturation [ 30 , 31 , 32 ]. Moreover, IFN-α can synergize with polyinosinic:polycytidylic acid (p-I:C) and the “classical” type-1-polarizing cytokine cocktail, allowing for serum-free generation of fully mature type-1-polarized DC (DC1) [ 33 , 34 ], providing DC with different chemoattractive properties [ 35 ].…”