Defective Regulation of Membrane TNFα Expression in Dendritic Cells of Glioblastoma Patients Leads to the Impairment of Cytotoxic Activity Against Autologous Tumor Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Apr 25

PMID 32326230

Citations 2

Authors

Tamara Tyrinova

Olga Leplina

Sergey Mishinov

Marina Tikhonova

Evgeniya Dolgova

Anastasiya Proskurina

Vyacheslav Stupack

Sergey Bogachev

Alexander Ostanin

Elena Chernykh

Affiliations

Soon will be listed here.

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.

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