Defective regulation of membrane TNFα expression in dendritic cells of glioblastoma patients leads to the impairment of cytotoxic activity against autologous tumor cells

Tamara Tyrinova, Olga Leplina, Sergey Mishinov, Marina Tikhonova, Evgeniya Dolgova, Anastasiya Proskurina, Vyacheslav Stupack, Sergey Bogachev, Alexander Ostanin, Elena Chernykh

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number2898
Number of pages19
JournalInternational Journal of Molecular Sciences
Volume21
Issue number8
DOIs
Publication statusPublished - 21 Apr 2020

Keywords

  • Dendritic cells
  • Glioblastoma
  • Granule-dependent cytotoxicity
  • TACE/ADAM-17
  • TNFα
  • GLIOMA-CELLS
  • PATHWAYS
  • INTERLEUKIN-2
  • FAS LIGAND
  • APOPTOSIS
  • TNF alpha
  • ACTIVATED PROTEIN-KINASE
  • TRAIL
  • granule-dependent cytotoxicity
  • INTERFERON-ALPHA
  • IN-VITRO
  • dendritic cells
  • glioblastoma
  • ANTIGEN

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