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 -