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Poster Display session

357 - Glioblastoma multiforme cells are sensitive to lysis mediated by killer dendritic cells via granule-dependent and death receptor-dependent mechanisms of cytotoxicity

Date

14 Dec 2018

Session

Poster Display session

Presenters

Tamara Tyrinova

Citation

Annals of Oncology (2018) 29 (suppl_10): x11-x16. 10.1093/annonc/mdy485

Authors

T. Tyrinova1, O. Leplina1, S. Mishinov2, M. Tikhonova1, A. Kalinovskiy3, S. Chernov3, V. Stupak2, A. Ostanin1, E. Chernykh1

Author affiliations

  • 1 Laboratory Of Cellular Immunotherapy, Research Institute of Fundamental and Clinical Immunology, 630099 - Novosibirsk/RU
  • 2 Neurosurgery Department, Novosibirsk Research Institute of Traumatology and Orthopedics them. Y.L.Tsivyana, 630091 - Novosibirsk/RU
  • 3 Neurosurgery Department, Federal Neurosurgical Center, 630087 - Novosibirsk/RU
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Abstract 357

Background

Glioblastoma multiforme (GB) is the most common type of primary brain tumors, that virtually always relapses, despite initial treatment with surgical resection, radio- and chemotherapy. Nowadays new promising approaches are developed in treating GB based on dendritic cell (DC) vaccines for the enhancement of the anti-tumor immune response. IFNα-induced monocyte-derived DCs possess properties of myeloid DCs, plasmacytoid DCs and NK cells. The present study focuses on the role of death-inducing mechanisms in DC cytotoxicity against GB cells.

Methods

The study was conducted in 26 donors and 21 GB patients. DCs were generated by culturing of plastic-adherent peripheral blood mononuclear cells in the presence of GM-CSF and IFN-α followed by the addition of LPS. The tumor cell lines were obtained from tissues of 14 GB patients. DC cytotoxicity against tumor cells was studied using MTT-assay.

Results

Donor DCs induced death of GB cell lines (min-max cytotoxicity 11-80%). The lysis of GB cells was accompanied with the increase of Annexin V+ apoptotic tumor cells. GB cells expressed death receptors TNF-R1, TRAIL-R2 and Fas. To examine death receptor-mediated killer activity, donor DC were pretreated with soluble forms of TNF family receptors. The blocking of TNF-R1-signaling pathway decreased DC cytotoxicity against GB cells by 25% on average. rhTRAIL-R2 or rhFas pretreatment slightly abolished DC cytotoxicity (with an average of 10%). The most blocking effect on DC cytotoxicity against GB cells was observed if DCs were pretreated with concanamicin A, an inhibitor of granule-dependent killing (Δ up to 60%). GB patient DCs were characterized by reduced cytotoxicity against autologous GB cell lines compared to donor values. Low cytotoxicity of patient DCs was associated with decreased level of membrane TNFα (mTNFα), but intact FasL, TRAIL, perforin and granzyme B molecule expression. The addition of IL-2 into patient DCs enhanced cytotoxicity of DCs towards autologous GB cells and increased mTNFα expression on DCs.

Conclusions

Thus, DCs with tumoricidal activity and ex vivo regulation of DC cytotoxic function may become a new approach to obtain effective anti-tumor DC-vaccines.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Elena Chernykh.

Funding

Grant of the Foundation of the President of the Russian Federation.

Disclosure

All authors have declared no conflicts of interest.

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