TRAIL+ Human Plasmacytoid Dendritic Cells Kill Tumor Cells In Vitro: Mechanisms of Imiquimod- and IFN- -Mediated Antitumor Reactivity

Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria.
The Journal of Immunology (Impact Factor: 4.92). 02/2012; 188(4):1583-91. DOI: 10.4049/jimmunol.1102437
Source: PubMed


Dendritic cells (DCs) not only exhibit the unique capacity to evoke primary immune responses, but may also acquire TLR-triggered cytotoxic activity. We and others have previously shown that TLR7/8- and TLR9-stimulated plasmacytoid DCs (pDCs) isolated from human peripheral blood express the effector molecule TRAIL. The exact mechanisms through which pDCs acquire and elicit their cytotoxic activity are still not clear. We now show that in the absence of costimulators, TRAIL induction on pDCs occurs with agonists to intracellular TLRs only and is accompanied by a phenotypic as well as functional maturation, as evidenced by a comparatively superior MLR stimulatory capacity. pDCs acquired TRAIL in an IFN-α/β-dependent fashion and, notably, TRAIL expression on pDCs could be induced by IFN-α stimulation alone. At a functional level, both TLR7/8- (imiquimod [IMQ]) and TLR9-stimulated (CpG2216) pDCs lysed Jurkat T cells in a TRAIL- and cell contact-dependent fashion. More importantly, IFN-α-activated pDCs acquired similar cytotoxic properties, independent of TLR stimulation and maturation. Both IMQ- and IFN-α-activated pDCs could also lyse certain melanoma cell lines in a TRAIL-dependent fashion. Interestingly, suboptimal doses of IMQ and IFN-α exhibited synergistic action, leading to optimal TRAIL expression and melanoma cell lysis by pDCs. Our data imply that tumor immunity in patients receiving adjuvant IMQ and/or IFN-α may involve the active participation of cytotoxic pDCs.

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Available from: Madeleine L Tschernitz, Aug 19, 2014
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    • "Strikingly, the number of BDCA-2 + cells significantly inversely correlated with healing duration (Fig. 1d). We next performed quantitative RT-PCR for cytokines and cytotoxic molecules, which have been documented to be involved in IMQ-mediated tumor clearance [6] [7] [9], including IFN-a, TNF-a, perforin, Gzmb, TRAIL and FasL (Detailed methods; See supplementary material). As expected, mRNA expression of IFN-a and TNF-a in inflamed AK lesions significantly increased at approximately 30-and 10-fold respectively (Fig. 2a). "
    Journal of Dermatological Science 10/2014; 76(1). DOI:10.1016/j.jdermsci.2014.07.004 · 3.42 Impact Factor
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    • "We then focused on the CD1c+ DC and pDC interaction. Apoptosis of CD1c+ DCs was not affected by pDCs excluding that pDCs killed CD1c+ DCs through type I IFN or GrB-mediated mechanisms (22, 23) (Figures 5A,B). Similarly, pDCs did not affect the number of Mtb-infected CD1c+ DCs (Figure 5C). "
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    ABSTRACT: Human primary dendritic cells (DCs) are heterogeneous by phenotype, function, and tissue localization and distinct from inflammatory monocyte-derived DCs. Current information regarding the susceptibility and functional role of primary human DC subsets to Mycobacterium tuberculosis (Mtb) infection is limited. Here, we dissect the response of different primary DC subsets to Mtb infection. Myeloid CD11c(+) cells and pDCs (C-type lectin 4C(+) cells) were located in human lymph nodes (LNs) of tuberculosis (TB) patients by histochemistry. Rare CD141(hi) DCs (C-type lectin 9A(+) cells) were also identified. Infection with live Mtb revealed a higher responsiveness of myeloid CD1c(+) DCs compared to CD141(hi) DCs and pDCs. CD1c(+) DCs produced interleukin (IL)-6, tumor necrosis factor α, and IL-1β but not IL-12p70, a cytokine important for Th1 activation and host defenses against Mtb. Yet, CD1c(+) DCs were able to activate autologous naïve CD4(+) T cells. By combining cell purification with fluorescence-activated cell sorting and gene expression profiling on rare cell populations, we detected in responding CD4(+) T cells, genes related to effector-cytolytic functions and transcription factors associated with Th1, Th17, and Treg polarization, suggesting multifunctional properties in our experimental conditions. Finally, immunohistologic analyses revealed contact between CD11c(+) cells and pDCs in LNs of TB patients and in vitro data suggest that cooperation between Mtb-infected CD1c(+) DCs and pDCs favors stimulation of CD4(+) T cells.
    Frontiers in Immunology 07/2014; 5:324. DOI:10.3389/fimmu.2014.00324
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    • "As previously discussed, in relation to the T cell/pDC interaction, activated pDCs express TRAIL, which induces an apoptotic process by binding to the TRAIL receptors. Tumor cells are known to be sensitive to TRAIL, and via this interaction could directly induce tumor cell apoptosis (171). Avoiding this apoptotic pathway by downregulation of TRAIL has been reported for several cancers by numerous studies (173). "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a specific subset of naturally occurring dendritic cells, that secrete large amounts of Type I interferon and play an important role in the immune response against viral infection. Several studies have highlighted that they are also effective antigen presenting cells, making them an interesting target for immunotherapy against cancer. However, the modes of action of pDCs are not restricted to antigen presentation and IFN secretion alone. In this review we will highlight a selection of cell surface proteins expressed by human pDCs that may facilitate communication with other immune cells, and we will discuss the implications of these molecules for pDC-driven immune responses.
    Frontiers in Immunology 11/2013; 4:372. DOI:10.3389/fimmu.2013.00372
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