Abstract
Dendritic cells (DCs) of patients with high-grade brain glioma exhibit impaired expression of membrane TNFα associated with low DC cytotoxicity against TNF-R1-expressing tumor cell line HEp-2. To assess the significance of these findings, we investigated a role of TNFα/TNF-R1-signaling pathway in DC cytotoxic activity against allogenic and autologous cell lines obtained from high-grade glioma tissues. DCs were generated by culturing of plastic-adherent peripheral blood mononuclear cells in presence of GM-CSF and IFNα for 4 d followed by LPS addition for 24 h (IFN-DCs). The tumor cell lines were obtained from tissues of 11 patients with glioblastoma multiforme. According our findings glioblastoma cells were sensitive to lysis mediated by donor IFN-DCs. The level of DC cytotoxic effect against cell lines obtained from different glioma patient tissues varied from 20 to 72.2%. DC lysis of 8 out of 11 glioblastoma cell lines exceeded 40%. Glioblastoma cell lines expressed both TNF-R1 and TNF-R2 receptors, but mostly – TNF-R1. However, rTNFα did not show cytotoxic activity towards glioblastoma cell lines. Blocking of TNFα/TNF-R1-signaling pathway by treating of donor IFN-DCs with soluble rhTNFR1 receptor led to partial decrease of DC cytotoxic activity against 5 out of 6 tested glioblastoma cell lines by 11-40% (median of suppression 24%). Glioblastoma patient IFN-DCs which were characterized by an impairment of TNFα/TNF-R1-signaling pathway lysed these glioblastoma cell lines, however median of DC cytotoxicity was 30% lower than that of donor values (31.5 vs 45.1%; р = 0.003). Cytotoxic activity of IFN-DCs of the glioblastoma patient against autologous tumor cells resistance to TNFα/TNF-R1-signaling pathway was comparable with level of cytotoxicity of donor IFN-DCs. Thus, glioblastoma cells are sensitive to cytotoxic activity of DCs mediated via TNFα/TNF-R1-signaling pathway, but the defect of this mechanism in IFN-DCs of glioblastoma patients determines significant decrease of DC cytotoxicity towards glioblastoma cells.
Highlights
Согласно данным литературы, индукторами цитотоксической активности Дендритные клетки (ДК) являются интерфероны I типа (IFN I) [7, 15]
To assess the significance of these findings, we investigated a role of TNFα/TNF-R1-signaling pathway in Dendritic cells (DCs) cytotoxic activity against allogenic and autologous cell lines obtained from high-grade glioma tissues
Chernykh E.R., PhD, MD (Medicine), Professor, Corresponding Member, Russian Academy of Sciences, Head, Laboratory of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology, Novosibirsk, Russian Federation
Summary
Тыринова Т.В.1, Мишинов С.В.2, Леплина О.Ю.1, Альшевская А.А.1, Курочкина Ю.Д.1, Олейник Е.А.1, Калиновский А.В.3, Лопатникова Ю.А.1, Чернов С.В.3, Ступак В.В.2, Сенников С.В.1, Останин А.А.1, Черных Е.Р.1. Блокирование TNFα/TNF-R1-сигнального пути путем обработки IFN-ДК доноров растворимым рецептором rhTNFR1 снижало цитотоксическую активность ДК против 5 из 6 тестируемых глиобластомных линий на 11-40% (медиана супрессии – 24%). ДК больных глиобластомой с дефектом TNFα/TNF-R1-сигнального пути лизировали клетки этих глиобластомных линий, однако медианный уровень цитотоксичности был на 30% ниже, чем аналогичный показатель у доноров (31,5 vs 45,1%; р = 0,003). Черных «Роль TNFα/TNF-R1-сигнального пути в реализации цитотоксического эффекта дендритных клеток против глиобластомных линий» // Медицинская иммунология, 2018. Опухолевые клетки глиобластомных линий чувствительны к цитотоксическому эффекту ДК, опосредованному через TNFα/TNF-R1-сигнальный путь, и дефектность данного механизма у больных детерминирует значимое снижение цитотоксической активности ДК против глиобластомных клеток. Ключевые слова: дендритные клетки, интерферон-альфа, фактор некроза опухоли альфа, TNF-R1, глиобластома
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