Abstract
Besides an antigen-presenting function and ability to induce antitumor immune responses, dendritic cells (DCs) possess a direct tumoricidal activity. We previously reported that monocyte-derived IFNα-induced DCs (IFN-DCs) of glioblastoma multiforme patients express low levels of membrane TNFα molecule (mTNFα) and have impaired TNFα/TNF-R1-mediated cytotoxicity against immortalized tumor cell line HEp-2. However, whether the observed defect could affect killer activity of glioma patient DCs against autologous tumor cells remained unclear. Here, we show that donor IFN-DCs possess cytotoxic activity against glioblastoma cell lines derived from a primary tumor culture. Granule-mediated and TNFα/TNF-R1-dependent pathways were established as the main mechanisms underlying cytotoxic activity of IFN-DCs. Glioblastoma patient IFN-DCs showed lower cytotoxicity against autologous glioblastoma cells sensitive to TNFα/TNFR1-mediated lysis, which was associated with low TNFα mRNA expression and high TACE/ADAM-17 enzyme activity. Recombinant IL-2 (rIL-2) and human double-stranded DNA (dsDNA) increased 1.5-fold cytotoxic activity of patient IFN-DCs against autologous glioblastoma cells. dsDNA, but not rIL-2, enhanced the expression of TNFα mRNA and decreased expression and activity of TACE/ADAM-17 enzyme. In addition, dsDNA and rIL-2 stimulated the expression of perforin and granzyme B (in the presence of dsDNA), suggesting the possibility of enhancing DC cytotoxicity against autologous glioblastoma cells via various mechanisms.
Highlights
Dendritic cells (DCs) play a key role in antitumor immune responses due to their ability to present tumor antigens to naive T cells, as well as to induce generation of cytotoxic CD8+ T lymphocytes [1,2]
IFN-DCs exhibit cytotoxic activity against various tumor cell lines, express a wide range of cytotoxic ligands (TNFα, TRAIL, FasL, perforin), and secrete granzyme B, which is barely produced by IL-4-DCs [5,9]
We evaluate cytotoxic activity of IFNα-induced dendritic cells against glioblastoma cell lines obtained from primary tumor cell cultures, and investigated the mechanisms underlying DC-mediated glioblastoma cell lysis
Summary
Dendritic cells (DCs) play a key role in antitumor immune responses due to their ability to present tumor antigens to naive T cells, as well as to induce generation of cytotoxic CD8+ T lymphocytes [1,2]. In the past 20 years, in addition to antigen-presenting function and the ability to stimulate immune responses, DCs have been shown to exhibit cytotoxic activity in that they can directly cause tumor cell death via granule- and death receptor-mediated mechanisms [3,4]. The former mechanism is associated with the release of perforin and granzyme B cytotoxic mediators from lytic granules of DCs [5,6,7]. We elucidated molecular mechanisms of impaired cytotoxicity, as well as analyzed approaches to enhance effector DC functions
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