Defective regulation of membrane TNFα expression in dendritic cells of glioblastoma patients leads to the impairment of cytotoxic activity against autologous tumor cells. / Tyrinova, Tamara; Leplina, Olga; Mishinov, Sergey et al.
In: International Journal of Molecular Sciences, Vol. 21, No. 8, 2898, 21.04.2020.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Defective regulation of membrane TNFα expression in dendritic cells of glioblastoma patients leads to the impairment of cytotoxic activity against autologous tumor cells
AU - Tyrinova, Tamara
AU - Leplina, Olga
AU - Mishinov, Sergey
AU - Tikhonova, Marina
AU - Dolgova, Evgeniya
AU - Proskurina, Anastasiya
AU - Stupack, Vyacheslav
AU - Bogachev, Sergey
AU - Ostanin, Alexander
AU - Chernykh, Elena
PY - 2020/4/21
Y1 - 2020/4/21
N2 - 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.
AB - 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.
KW - Dendritic cells
KW - Glioblastoma
KW - Granule-dependent cytotoxicity
KW - TACE/ADAM-17
KW - TNFα
KW - GLIOMA-CELLS
KW - PATHWAYS
KW - INTERLEUKIN-2
KW - FAS LIGAND
KW - APOPTOSIS
KW - TNF alpha
KW - ACTIVATED PROTEIN-KINASE
KW - TRAIL
KW - granule-dependent cytotoxicity
KW - INTERFERON-ALPHA
KW - IN-VITRO
KW - dendritic cells
KW - glioblastoma
KW - ANTIGEN
UR - http://www.scopus.com/inward/record.url?scp=85083966495&partnerID=8YFLogxK
U2 - 10.3390/ijms21082898
DO - 10.3390/ijms21082898
M3 - Article
C2 - 32326230
AN - SCOPUS:85083966495
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 8
M1 - 2898
ER -
ID: 24190768