Defective Dendritic Cell Cytotoxic Activity of High-Grade Glioma Patients' Results from the Low Expression of Membrane TNFα and Can Be Corrected<i>In Vitro</i>by Treatment with Recombinant IL-2 or Exogenic Double-Stranded DNA

Тыринова, Т. В.; Леплина, О. Ю.; Мишинов, С. В.; Тихонова, М. А.; Kalinovskiy, А. V.; Чернов, С. В.; Долгова, Е. В.; Stupak, V. V.; Voronina, Evgeniya; Bogachev, Sergey S.; Shevela, Е. Ya.; Ostanin, А. А.; Черных, Е. Р.

doi:10.1089/jir.2017.0084

Cited by 7 publications

(11 citation statements)

References 56 publications

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“…We have previously shown that IFN-DCs from glioblastoma patients are characterized by decreased expression of mTNFα, compared to donor IFN-DCs [18]. Here, we show that expression of other molecules involved in DC cytotoxic activity in glioblastoma patients is preserved.…”

Section: Ifn-dcs From Glioblastoma Patients Do Not Differ From Donor mentioning

confidence: 46%

“…Interestingly, the level of reduction in most cases corresponded to the intensity of rTNF-R1-mediated inhibitory effect, i.e., accounted for a fraction of the total cytotoxic potential mediated by TNFα/TNF-R1-dependent mechanism. We envisage that low mTNFα expression levels on IFN-DCs derived from glioblastoma patients reported in our previous study [18] could be a putative key factor contributing to the impairment of the cytotoxic DC activity against autologous tumor cells.…”

Section: Discussionmentioning

confidence: 82%

“…We have previously shown that recombinant interleukin 2 (rIL-2) and human double-stranded DNA (dsDNA) enhanced the expression of mTNFα on IFN-DCs from glioblastoma patients [18]. Our observations could be important for developing possible correction methods of impaired cytotoxic DC activity derived from glioblastoma patients against autologous tumor cells sensitive to TNFα/TNF-R1-dependent lysis.…”

Section: Ril-2 and Dsdna Up-regulate Ifn-dc Cytotoxic Activity Againsmentioning

confidence: 76%

“…In this case, high activity of TACE/ADAM-17 in DCs can also promote tumor growth via inhibition of the cytotoxic DC activity by way of decreasing mTNFα levels. However, inhibition of TACE/ADAM-17 reduces mTNFα shedding on IFN-DC membranes and enhances the cytotoxic DC activity against TNFα/TNF-R1-sensitive tumor cells [18].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies showed that IFN-DCs from patients with high-grade gliomas (glioblastoma multiforme) in contrast to DCs derived from patients with low-grade gliomas are characterized by impaired TNFα/TNF-R-dependent cytotoxicity. This defect manifests itself in the reduced ability of IFN-DCs to lyse HEp-2 laryngeal carcinoma cells (which are selectively sensitive to TNFα/TNF-R1-mediated lysis), and this defect has been shown to be associated with low expression levels characteristic of the membrane form of TNFα (mTNFα) present on patient-derived DCs [17,18].…”

Section: Introductionmentioning

confidence: 99%

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

Тыринова

Леплина

Мишинов

et al. 2020

IJMS

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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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Section: Ifn-dcs From Glioblastoma Patients Do Not Differ From Donor mentioning

confidence: 46%

Section: Discussionmentioning

confidence: 82%

Section: Ril-2 and Dsdna Up-regulate Ifn-dc Cytotoxic Activity Againsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Тыринова

Леплина

Мишинов

et al. 2020

IJMS

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Epitope mapping of novel monoclonal antibodies to human angiotensin I‐converting enzyme

et al. 2021

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Angiotensin I-converting enzyme (ACE, CD143) plays a crucial role in blood pressure regulation, vascular remodeling, and immunity. A wide spectrum of mAbs to different epitopes on the N and C domains of human ACE have been generated and used to study different aspects of ACE biology, including establishing a novel approach-conformational fingerprinting. Here we characterized a novel set of 14 mAbs, developed against human seminal fluid ACE. The epitopes for these novel mAbs were defined using recombinant ACE constructs with truncated N and C domains, species cross-reactivity, ACE mutagenesis, and competition with the previously mapped anti-ACE mAbs. Nine mAbs recognized regions on the N domain, and 5 mAbs-on the C domain of ACE. The epitopes for most of these novel mAbs partially overlap with epitopes mapped onto ACE by the previously generated mAbs, whereas mAb 8H1 recognized yet unmapped region on the C domain where three ACE mutations associated with Alzheimer's disease are localized and is a marker for ACE mutation T877M. mAb 2H4 could be considered as a specific marker for ACE in dendritic cells. This novel set of mAbs can identify even subtle changes in human ACE conformation caused by tissue-specific glycosylation of ACE or mutations, and can detect human somatic and testicular ACE in biological fluids and tissues. Furthermore, the high reactivity of these novel mAbs provides an Isolda A. Popova and Lizelle Lubbe contributed equally.

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Human dendritic cell subsets in the glioblastoma-associated microenvironment

Hu¹,

Jiang²,

Gao³

et al. 2023

Journal of Neuroimmunology

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Defective Dendritic Cell Cytotoxic Activity of High-Grade Glioma Patients' Results from the Low Expression of Membrane TNFα and Can Be CorrectedIn Vitroby Treatment with Recombinant IL-2 or Exogenic Double-Stranded DNA

Cited by 7 publications

References 56 publications

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

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

Epitope mapping of novel monoclonal antibodies to human angiotensin I‐converting enzyme

Human dendritic cell subsets in the glioblastoma-associated microenvironment

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