Establishment and immune phenotyping of patient-derived glioblastoma models in humanized mice
Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the c...
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Published in | Frontiers in immunology Vol. 14; p. 1324618 |
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Main Authors | , , , , , , , |
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Language | English |
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11.01.2024
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Abstract | Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM (hGBM) models in humanized mice using patient-derived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBM tumor engraftment and growth in bone marrow-liver-thymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBM biology within the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM. |
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AbstractList | Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM (hGBM) models in humanized mice using patient-derived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBM tumor engraftment and growth in bone marrow-liver-thymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBM biology within the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM. Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM (hGBM) models in humanized mice using patient-derived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBM tumor engraftment and growth in bone marrow-liver-thymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBM biology within the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM.Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models generated using mouse tumor cells play a pivotal role in testing the therapeutic efficacy of emerging immune-based therapies for GBMs. However, the clinical translatability of such studies is limited as mouse tumor lines do not fully recapitulate GBMs seen in inpatient settings. In this study, we generated three distinct, imageable human-GBM (hGBM) models in humanized mice using patient-derived GBM cells that cover phenotypic and genetic GBM heterogeneity in primary (invasive and nodular) and recurrent tumors. We developed a pipeline to first enrich the tumor-initiating stem-like cells and then successfully established robust patient-derived GBM tumor engraftment and growth in bone marrow-liver-thymus (BLT) humanized mice. Multiplex immunofluorescence of GBM tumor sections revealed distinct phenotypic features of the patient GBM tumors, with myeloid cells dominating the immune landscape. Utilizing flow cytometry and correlative immunofluorescence, we profiled the immune microenvironment within the established human GBM tumors in the BLT mouse models and showed tumor infiltration of variable human immune cells, creating a unique immune landscape compared with lymphoid organs. These findings contribute substantially to our understanding of GBM biology within the context of the human immune system in humanized mice and lay the groundwork for further translational studies aimed at advancing therapeutic strategies for GBM. |
Author | Liu, Longsha van Schaik, Thijs A Shah, Khalid Borges, Paulo Vrbanac, Vladimir Chen, Kok-Siong Rossignoli, Filippo Wakimoto, Hiroaki |
AuthorAffiliation | 2 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School , Boston, MA , United States 3 Humanized Immune System Mouse Program, Ragon Institute, Massachusetts General Hospital, Harvard Medical School , Boston, MA , United States 1 Center for Stem Cell and Translational Immunotherapy (CSTI), Harvard Medical School , Boston, MA , United States 4 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA , United States 5 Harvard Stem Cell Institute, Harvard University , Cambridge, MA , United States |
AuthorAffiliation_xml | – name: 3 Humanized Immune System Mouse Program, Ragon Institute, Massachusetts General Hospital, Harvard Medical School , Boston, MA , United States – name: 4 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School , Boston, MA , United States – name: 2 Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School , Boston, MA , United States – name: 1 Center for Stem Cell and Translational Immunotherapy (CSTI), Harvard Medical School , Boston, MA , United States – name: 5 Harvard Stem Cell Institute, Harvard University , Cambridge, MA , United States |
Author_xml | – sequence: 1 givenname: Longsha surname: Liu fullname: Liu, Longsha organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States – sequence: 2 givenname: Thijs A surname: van Schaik fullname: van Schaik, Thijs A organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States – sequence: 3 givenname: Kok-Siong surname: Chen fullname: Chen, Kok-Siong organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States – sequence: 4 givenname: Filippo surname: Rossignoli fullname: Rossignoli, Filippo organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States – sequence: 5 givenname: Paulo surname: Borges fullname: Borges, Paulo organization: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States – sequence: 6 givenname: Vladimir surname: Vrbanac fullname: Vrbanac, Vladimir organization: Humanized Immune System Mouse Program, Ragon Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States – sequence: 7 givenname: Hiroaki surname: Wakimoto fullname: Wakimoto, Hiroaki organization: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States – sequence: 8 givenname: Khalid surname: Shah fullname: Shah, Khalid organization: Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States |
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Copyright | Copyright © 2024 Liu, van Schaik, Chen, Rossignoli, Borges, Vrbanac, Wakimoto and Shah. Copyright © 2024 Liu, van Schaik, Chen, Rossignoli, Borges, Vrbanac, Wakimoto and Shah 2024 Liu, van Schaik, Chen, Rossignoli, Borges, Vrbanac, Wakimoto and Shah |
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Keywords | GBM - multiforme flow cytometry hGBM BLT humanized mice multiplex immunofluorescence staining humanized mice |
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License | Copyright © 2024 Liu, van Schaik, Chen, Rossignoli, Borges, Vrbanac, Wakimoto and Shah. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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Snippet | Glioblastoma (GBM) is the most aggressive and common type of malignant brain tumor diagnosed in adults. Preclinical immunocompetent mouse tumor models... |
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StartPage | 1324618 |
SubjectTerms | Adult Animals BLT humanized mice Brain Neoplasms Disease Models, Animal flow cytometry GBM - multiforme Glioblastoma - therapy hGBM humanized mice Humans Immunology Mice multiplex immunofluorescence staining Neoplasm Recurrence, Local - pathology Neoplastic Stem Cells - pathology Tumor Microenvironment |
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Title | Establishment and immune phenotyping of patient-derived glioblastoma models in humanized mice |
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