Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice
The tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macropha...
| Autores: | , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:289015 |
| Acceso en línea: | https://ddd.uab.cat/record/289015 https://dx.doi.org/urn:doi:10.3390/ijms242417628 |
| Access Level: | acceso abierto |
| Palabra clave: | MR spectroscopic imaging PD-L1 Glioblastoma Macrophages Metalloproteases Shedding Temozolomide Therapy |
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Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in MiceZhao, Kai|||0009-0000-5186-2952Calero-Perez, Pilar|||0000-0001-9370-3757Bopp, Miriam H.A.|||0000-0003-1574-7572Möschl, VincentPagenstecher, Axel|||0000-0001-9627-6439Mulero-Acevedo, Marta|||0000-0002-3600-8907Vázquez, MarioBarcia, Carlos|||0000-0003-0976-4245Arús i Caraltó, Carles|||0000-0003-2510-2671Nimsky, Christopher|||0000-0002-8216-9410Rusch, Tillmann|||0009-0007-4848-5464Bartsch, Joerg Walter.|||0000-0002-2773-3357Candiota Silveira, Ana Paula|||0000-0002-1523-6505MR spectroscopic imagingPD-L1GlioblastomaMacrophagesMetalloproteasesSheddingTemozolomideTherapyThe tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent "imprinting" mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage-tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8. 22023-01-0120232023-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/289015https://dx.doi.org/urn:doi:10.3390/ijms242417628reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-128717OB-I00Ministerio de Sanidad y Consumo CB06/01/0010open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2890152026-06-06T12:50:31Z |
| dc.title.none.fl_str_mv |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| title |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| spellingShingle |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice Zhao, Kai|||0009-0000-5186-2952 MR spectroscopic imaging PD-L1 Glioblastoma Macrophages Metalloproteases Shedding Temozolomide Therapy |
| title_short |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| title_full |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| title_fullStr |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| title_full_unstemmed |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| title_sort |
Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice |
| dc.creator.none.fl_str_mv |
Zhao, Kai|||0009-0000-5186-2952 Calero-Perez, Pilar|||0000-0001-9370-3757 Bopp, Miriam H.A.|||0000-0003-1574-7572 Möschl, Vincent Pagenstecher, Axel|||0000-0001-9627-6439 Mulero-Acevedo, Marta|||0000-0002-3600-8907 Vázquez, Mario Barcia, Carlos|||0000-0003-0976-4245 Arús i Caraltó, Carles|||0000-0003-2510-2671 Nimsky, Christopher|||0000-0002-8216-9410 Rusch, Tillmann|||0009-0007-4848-5464 Bartsch, Joerg Walter.|||0000-0002-2773-3357 Candiota Silveira, Ana Paula|||0000-0002-1523-6505 |
| author |
Zhao, Kai|||0009-0000-5186-2952 |
| author_facet |
Zhao, Kai|||0009-0000-5186-2952 Calero-Perez, Pilar|||0000-0001-9370-3757 Bopp, Miriam H.A.|||0000-0003-1574-7572 Möschl, Vincent Pagenstecher, Axel|||0000-0001-9627-6439 Mulero-Acevedo, Marta|||0000-0002-3600-8907 Vázquez, Mario Barcia, Carlos|||0000-0003-0976-4245 Arús i Caraltó, Carles|||0000-0003-2510-2671 Nimsky, Christopher|||0000-0002-8216-9410 Rusch, Tillmann|||0009-0007-4848-5464 Bartsch, Joerg Walter.|||0000-0002-2773-3357 Candiota Silveira, Ana Paula|||0000-0002-1523-6505 |
| author_role |
author |
| author2 |
Calero-Perez, Pilar|||0000-0001-9370-3757 Bopp, Miriam H.A.|||0000-0003-1574-7572 Möschl, Vincent Pagenstecher, Axel|||0000-0001-9627-6439 Mulero-Acevedo, Marta|||0000-0002-3600-8907 Vázquez, Mario Barcia, Carlos|||0000-0003-0976-4245 Arús i Caraltó, Carles|||0000-0003-2510-2671 Nimsky, Christopher|||0000-0002-8216-9410 Rusch, Tillmann|||0009-0007-4848-5464 Bartsch, Joerg Walter.|||0000-0002-2773-3357 Candiota Silveira, Ana Paula|||0000-0002-1523-6505 |
| author2_role |
author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
MR spectroscopic imaging PD-L1 Glioblastoma Macrophages Metalloproteases Shedding Temozolomide Therapy |
| topic |
MR spectroscopic imaging PD-L1 Glioblastoma Macrophages Metalloproteases Shedding Temozolomide Therapy |
| description |
The tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent "imprinting" mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage-tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2 2023-01-01 2023 2023-01-01 |
| dc.type.none.fl_str_mv |
Article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://ddd.uab.cat/record/289015 https://dx.doi.org/urn:doi:10.3390/ijms242417628 |
| url |
https://ddd.uab.cat/record/289015 https://dx.doi.org/urn:doi:10.3390/ijms242417628 |
| dc.language.none.fl_str_mv |
Inglés eng |
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Inglés |
| language |
eng |
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Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 PID2021-128717OB-I00 Ministerio de Sanidad y Consumo CB06/01/0010 |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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