Tumoricidal Potential of Native Blood Dendritic Cells: Direct Tumor Cell Killing and Activation of NK Cell-Mediated Cytotoxicity

Abstract

Dendritic cells (DCs) are characterized by their unique capacity for primary T cell activation, providing the opportunity for DC-based cancer vaccination protocols. Novel findings reveal that besides their role as potent inducers of tumor-specific T cells, human DCs display additional antitumor effects. Most of these data were obtained with monocyte-derived DCs, whereas studies investigating native blood DCs are limited. In the present study, we analyze the tumoricidal capacity of M-DC8+ DCs, which represent a major subpopulation of human blood DCs. We demonstrate that IFN-γ-stimulated M-DC8+ DCs lyse different tumor cell lines but not normal cells. In addition, we show that tumor cells markedly enhance the production of TNF-α by M-DC8+ DCs via cell-to-cell contact and that this molecule essentially contributes to the killing activity of M-DC8+ DCs. Furthermore, we illustrate the ability of M-DC8+ DCs to promote proliferation, IFN-γ production, and tumor-directed cytotoxicity of NK cells. The M-DC8+ DC-mediated enhancement of the tumoricidal potential of NK cells is mainly dependent on cell-to-cell contact. These results reveal that, in addition to their crucial role in activating tumor-specific T cells, blood DCs exhibit direct tumor cell killing and enhance the tumoricidal activity of NK cells. These findings point to the pivotal role of DCs in triggering innate and adaptive immune responses against tumors.

The ‘kiss of death’ by dendritic cells to cancer cells

“…Interestingly, although others have reported that pDCs are poorly cytotoxic, 52,71 Stary et al 54 demonstrated that bloodderived pDCs kill tumor cells upon TLR-7/8 activation via a TRAIL-dependent mechanism. Palucka's group also recently described a CD2 þ pDC subset found in human blood that kills tumors in vitro in a TRAIL-dependent fashion (KA Palucka, 77 showed that the rat cytotoxic DCs express NKR-P2, an ortholog of mouse and human NKG2D.…”

slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells

“…In addition, they are potent inducers of primary antigen-specific T-cell responses in vitro 11 , and show a superior programming of Th1/Th17 cell polarization as compared with classical CD1c þ DCs 14 . Furthermore, slanDCs induce in vitro tumour-specific cytotoxic T cells and strongly promote natural killer (NK) cell proliferation, NK cytotoxic activity and, in cooperation with neutrophils, NK-derived interferon-gamma (IFNg) production [15][16][17] . However, since the identification and functional analysis of human slanDCs in cancer patients has not been explored yet, in this study, we investigated such an issue.…”

Acute myeloid leukemia cells fail to activate native human dendritic cells: a potential mechanism of immune evasion

“…In previous studies, we have shown that activated slanDCs produce large amounts of TNF-a, which essentially contributes to their tumor-directed cytotoxicity. 5,7 In addition, we have shown that activated slanDCs are principal producers of IL-12, which favors the differentiation of naive CD4 þ T cells into Th1 cells and is important in NK cell activation. 6,8 Blood samples were obtained from healthy donors with informed consent.…”

“…The failure to trigger slanDC activation efficiently can be explained by an insufficient expression of 'danger' molecules by AML cells and/or the production of inhibitory molecules. As a consequence, the capacity of slanDCs to mediate tumor-directed cytotoxicity 7 and to activate tumor-reactive NK cells 8 and T cells 6 may be impaired. In addition, we found that two AML cell samples significantly inhibit TNF-a and IL-12 secretion by activated slanDCs.…”

“…Recently, we defined 6-sulfo LacNAc (slan)DCs (formerly termed M-DC8 þ DCs) as a major subpopulation of proinflammatory myeloid human blood DCs, which mainly differ from other blood DC subsets by their selective phenotype (6- 5,6 Functional data revealed that slanDCs can mediate tumor-directed cytotoxicity and efficiently activate tumor-reactive NK cells and CD8 þ CTLs. 7 To get novel insights into the impact of primary human AML cells on native human DCs, we investigated the capacity of AML cells to modulate the secretion of TNF-a and IL-12 by slanDCs. In previous studies, we have shown that activated slanDCs produce large amounts of TNF-a, which essentially contributes to their tumor-directed cytotoxicity.…”