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Leukocyte different...
Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
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- Roche, Francis P. (author)
- Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab
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- Pietilä, Ilkka (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Kaito, Hiroshi (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Sjöström, Elisabet O. (author)
- Uppsala universitet,Vaskulärbiologi,Science for Life Laboratory, SciLifeLab
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- Sobotzki, Nadine (author)
- ETH Zürich, Department of Health Sciences and Technology & Institute of Molecular Systems Biology, Zürich, Switzerland
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- Noguer, Oriol (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Persson Skare, Tor (author)
- Uppsala universitet,Vaskulärbiologi
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- Essand, Magnus (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab
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- Wollscheid, Bernd (author)
- ETH Zürich, Department of Health Sciences and Technology & Institute of Molecular Systems Biology, Zürich, Switzerland.
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- Welsh, Michael, 1957- (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Claesson-Welsh, Lena (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi
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(creator_code:org_t)
- 2018
- 2018
- English.
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In: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 17:9, s. 1961-1972
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Abstract
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- The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
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- art (subject category)
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- By the author/editor
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Roche, Francis P ...
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Pietilä, Ilkka
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Kaito, Hiroshi
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Sjöström, Elisab ...
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Sobotzki, Nadine
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Noguer, Oriol
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Persson Skare, T ...
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Essand, Magnus
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Wollscheid, Bern ...
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Welsh, Michael, ...
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Claesson-Welsh, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Molecular Cancer ...
- By the university
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Uppsala University