CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression
Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively...
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The Company of Biologists
2019-09-01
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doaj-389ce9713eb24efbb4a1fad3618bc73e2021-06-02T13:16:46ZengThe Company of BiologistsBiology Open2046-63902019-09-018910.1242/bio.044552044552CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppressionMatteo Riva0Roxanne Wouters1Akila Weerasekera2Sarah Belderbos3David Nittner4Dietmar R. Thal5Thaïs Baert6Roberto Giovannoni7Willy Gsell8Uwe Himmelreich9Marc Van Ranst10An Coosemans11 Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven 3000, Belgium Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven 3000, Belgium Biomedical MRI, Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), KU Leuven, Leuven 3000, Belgium Biomedical MRI, Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, KU Leuven Center for Human Genetics - InfraMouse, VIB, University of Leuven, Leuven 3000, Belgium Laboratory of Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, KU Leuven, Leuven 3000, Belgium Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven 3000, Belgium Department of Medicine and Surgery, University of Milano-Bicocca, Monza 20900, Italy Biomedical MRI, Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), KU Leuven, Leuven 3000, Belgium Biomedical MRI, Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), KU Leuven, Leuven 3000, Belgium Laboratory for Clinical and Epidemiological Virology, Rega Institute for Medical Research, KU Leuven, Leuven 3000, Belgium Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven 3000, Belgium Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively characterized a new in vivo model based on the orthotopic implantation of CT-2A cells cultured in neurospheres (NS/CT-2A). Murine CT-2A methylcholanthrene-induced HGG cells (C57BL/6 background) were cultured in monolayers (ML) or NS and orthotopically inoculated in syngeneic animals. ML/CT-2A and NS/CT-2A tumors' characterization included the analysis of tumor growth, immune microenvironment, glioma stem cells (GSCs), vascularization and metabolites. The immuno-modulating properties of NS/CT-2A and ML/CT-2A cells on splenocytes were tested in vitro. Mice harboring NS/CT-2A tumors had a shorter survival than those harboring ML/CT-2A tumors (P=0.0033). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors showed more abundant GSCs (P=0.0002 and 0.0770 for Nestin and CD133, respectively) and regulatory T cells (Tregs, P=0.0074), and a strong tendency towards an increased vascularization (P=0.0503). There were no significant differences in metabolites' composition between NS/ and ML/CT-2A tumors. In vitro, NS were able to drive splenocytes towards a more immunosuppressive status by reducing CD8+ T cells (P=0.0354) and by promoting Tregs (P=0.0082), macrophages (MF, P=0.0019) and their M2 subset (P=0.0536). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors show a more aggressive phenotype with increased immunosuppression and GSCs proliferation. Because of these specific features, the NS/CT-2A model represents a clinically relevant platform in the search for new HGG treatments aimed at reducing immunosuppression and eliminating GSCs.http://bio.biologists.org/content/8/9/bio044552High-grade glioma modelCT-2AGlioma stem cellsImmunosuppressionTregs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matteo Riva Roxanne Wouters Akila Weerasekera Sarah Belderbos David Nittner Dietmar R. Thal Thaïs Baert Roberto Giovannoni Willy Gsell Uwe Himmelreich Marc Van Ranst An Coosemans |
spellingShingle |
Matteo Riva Roxanne Wouters Akila Weerasekera Sarah Belderbos David Nittner Dietmar R. Thal Thaïs Baert Roberto Giovannoni Willy Gsell Uwe Himmelreich Marc Van Ranst An Coosemans CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression Biology Open High-grade glioma model CT-2A Glioma stem cells Immunosuppression Tregs |
author_facet |
Matteo Riva Roxanne Wouters Akila Weerasekera Sarah Belderbos David Nittner Dietmar R. Thal Thaïs Baert Roberto Giovannoni Willy Gsell Uwe Himmelreich Marc Van Ranst An Coosemans |
author_sort |
Matteo Riva |
title |
CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
title_short |
CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
title_full |
CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
title_fullStr |
CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
title_full_unstemmed |
CT-2A neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
title_sort |
ct-2a neurospheres-derived high-grade glioma in mice: a new model to address tumor stem cells and immunosuppression |
publisher |
The Company of Biologists |
series |
Biology Open |
issn |
2046-6390 |
publishDate |
2019-09-01 |
description |
Recently, several promising treatments for high-grade gliomas (HGGs) failed to provide significant benefit when translated from the preclinical setting to patients. Improving the animal models is fundamental to overcoming this translational gap. To address this need, we developed and comprehensively characterized a new in vivo model based on the orthotopic implantation of CT-2A cells cultured in neurospheres (NS/CT-2A). Murine CT-2A methylcholanthrene-induced HGG cells (C57BL/6 background) were cultured in monolayers (ML) or NS and orthotopically inoculated in syngeneic animals. ML/CT-2A and NS/CT-2A tumors' characterization included the analysis of tumor growth, immune microenvironment, glioma stem cells (GSCs), vascularization and metabolites. The immuno-modulating properties of NS/CT-2A and ML/CT-2A cells on splenocytes were tested in vitro. Mice harboring NS/CT-2A tumors had a shorter survival than those harboring ML/CT-2A tumors (P=0.0033). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors showed more abundant GSCs (P=0.0002 and 0.0770 for Nestin and CD133, respectively) and regulatory T cells (Tregs, P=0.0074), and a strong tendency towards an increased vascularization (P=0.0503). There were no significant differences in metabolites' composition between NS/ and ML/CT-2A tumors. In vitro, NS were able to drive splenocytes towards a more immunosuppressive status by reducing CD8+ T cells (P=0.0354) and by promoting Tregs (P=0.0082), macrophages (MF, P=0.0019) and their M2 subset (P=0.0536). Compared to standard ML/CT-2A tumors, NS/CT-2A tumors show a more aggressive phenotype with increased immunosuppression and GSCs proliferation. Because of these specific features, the NS/CT-2A model represents a clinically relevant platform in the search for new HGG treatments aimed at reducing immunosuppression and eliminating GSCs. |
topic |
High-grade glioma model CT-2A Glioma stem cells Immunosuppression Tregs |
url |
http://bio.biologists.org/content/8/9/bio044552 |
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