The Involvement of TNF-α-Related Apoptosis-Inducing Ligand in the Enhanced Cytotoxicity of IFN-β-Stimulated Human Dendritic Cells to Tumor Cells

Abstract

TNF-α-related apoptosis-inducing ligand (TRAIL) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells. Dendritic cells (DCs), besides their role as APCs, now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells. Here, we report that both human CD34+ stem cell-derived DCs (CD34DCs) and human CD14+ monocyte-derived DCs (MoDCs) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL. Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes. The level of TRAIL expression remained constant until DC maturation. TRAIL expression on immature CD34DCs or MoDCs was greatly up-regulated after IFN-β stimulation. Moreover, IFN-β could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL-sensitive tumor cells, but LPS did not have such an effect. The up-regulation of TRAIL on IFN-β-stimulated DCs partially contributed to the increased cytotoxicity of DCs. Pretreatment of TRAIL-sensitive tumor cells with caspase-3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN-β-stimulated DCs. In contrast, NF-κB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS-stimulated DCs. Our studies demonstrate that IFN-β-stimulated DCs are functionally cytotoxic. Thus, an innate mechanism of DC-mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL. Subsequently, DCs act as APCs involved in the uptake, processing, and presentation of apoptotic tumor Ags to cross-prime CD8+ CTL cells.

Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells

“…Previous reports have demonstrated that human peripheral blood dendritic cells (PBDC) can express TRAIL and kill TRAIL-sensitive target cells, such as HL60, under certain circumstances. (7) To ascertain whether CBDC can kill tumor cells through TRAIL, HL60 was used as the target cell in our study. Based on the possible different sensitivity of variable tumor cells to cytotoxicity mediated by CBDC, the other hematopoietic tumor cells lines, including Jurkat and Daudi, were also used as target cells.…”

“…Based on the reports that activated human PBDC were effective in killing tumor cells via involvement of an membranebound TNF family apoptosis-inducing pathway, (7,8) we measured cell surface and cytoplasmic expression of three major members of TNF family, including TRAIL, FasL and TNF-α, on CBDC before and after LPS or IFN-γ stimulation. As revealed in Figure 4, TRAIL, FasL and TNF-α were weakly expressed on the surface of CBDC, and could not be up-regulated by LPS or IFN-γ stimulation.…”

“…Some reports have demonstrated that DC activated with IFN-β or IFN-γ were effective at killing a spectrum of tumor cells via involvement of an membrane-bound tumor necrosing factor (TNF) family apoptosisinducing pathway. (7,8) Human DC, generated from umbilical cord blood monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4, constitutes a promising source of vaccines in antitumor immunotherapy. However, there have been no reports concerning the killing of tumor cells by in vitro cultured cord blood DC (CBDC).…”

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

“…69,70 Human blood cDCs acquire the ability to kill tumor cells via TRAIL expression or TNF-a secretion, upon IFN-a or IFN-g stimulation, 52,71 and monocyte-derived DCs upon IFN-b stimulation or measles virus infection. 72,73 Immature DCs have also been shown to kill freshly isolated tumors. [74][75][76] Although in vitro-derived immature DCs kill target cells very efficiently at low effector/target ratios via an apoptotic mechanism involving DNA fragmentation, mitochondrial dysfunction, and late membrane disruption, the level of cytotoxicity found in the freshly isolated, immature DCs remains low and questionable.…”

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

“…[10][11][12][13] It has also been reported that activation of DCs with IFN-a or -b leads to upregulation of TNF-a-related apoptosis-inducing ligand (TRAIL) expression, and to direct tumoricidal activity mediated by DCs via TRAIL. 14,15 IFN-a-transduced tumor cells also activate and promote the survival of tumor-specific CD8 + CTLs in vivo. 16 Although the type I IFN protein has been used therapeutically for patients with malignant gliomas by systemic administration and its safety has been demonstrated, 17,18 it has been difficult to achieve effective cytokine levels within the tumor at clinically tolerated doses.…”