Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses
Abstract Background High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosi...
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Published in | Neuro-oncology (Charlottesville, Va.) Vol. 22; no. 6; pp. 806 - 818 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
US
Oxford University Press
09.06.2020
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Abstract | Abstract
Background
High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn’s role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion.
Methods
We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME.
Results
We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8−/− and CD4−/− immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME.
Conclusions
Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies. |
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AbstractList | High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn's role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion.
We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME.
We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8-/- and CD4-/- immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME.
Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies. Abstract Background High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn’s role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion. Methods We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME. Results We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8−/− and CD4−/− immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME. Conclusions Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies. BACKGROUNDHigh-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn's role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion. METHODSWe evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME. RESULTSWe demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8-/- and CD4-/- immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME. CONCLUSIONSGliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies. |
Author | Lowenstein, Pedro R Ventosa, Maria Núñez, Felipe J Argento, Anna E Patel, Priti Kadiyala, Padma Zhao, Lili Comba, Andrea Castro, Maria G Zamler, Daniel B Dunn, Patrick J |
AuthorAffiliation | 2 Department of Cell and Developmental Biology, University of Michigan Medical School , Ann Arbor, Michigan 4 Rogel Cancer Center, University of Michigan Medical School , Ann Arbor, Michigan 1 Department of Neurosurgery, University of Michigan Medical School , Ann Arbor, Michigan 3 Department of Biostatistics, University of Michigan Medical School , Ann Arbor, Michigan |
AuthorAffiliation_xml | – name: 3 Department of Biostatistics, University of Michigan Medical School , Ann Arbor, Michigan – name: 4 Rogel Cancer Center, University of Michigan Medical School , Ann Arbor, Michigan – name: 2 Department of Cell and Developmental Biology, University of Michigan Medical School , Ann Arbor, Michigan – name: 1 Department of Neurosurgery, University of Michigan Medical School , Ann Arbor, Michigan |
Author_xml | – sequence: 1 givenname: Andrea surname: Comba fullname: Comba, Andrea organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 2 givenname: Patrick J surname: Dunn fullname: Dunn, Patrick J organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 3 givenname: Anna E surname: Argento fullname: Argento, Anna E organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 4 givenname: Padma surname: Kadiyala fullname: Kadiyala, Padma organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 5 givenname: Maria surname: Ventosa fullname: Ventosa, Maria organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 6 givenname: Priti surname: Patel fullname: Patel, Priti organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 7 givenname: Daniel B surname: Zamler fullname: Zamler, Daniel B organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 8 givenname: Felipe J surname: Núñez fullname: Núñez, Felipe J organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 9 givenname: Lili surname: Zhao fullname: Zhao, Lili organization: Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 10 givenname: Maria G surname: Castro fullname: Castro, Maria G organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan – sequence: 11 givenname: Pedro R orcidid: 0000-0002-8427-4409 surname: Lowenstein fullname: Lowenstein, Pedro R email: pedrol@umich.edu organization: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31950181$$D View this record in MEDLINE/PubMed |
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Background
High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor... High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and... BACKGROUNDHigh-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment... |
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SubjectTerms | Animals Basic and Translational Investigations Brain Neoplasms - genetics Glioma - genetics Immunity Mice Proto-Oncogene Proteins c-fyn - genetics Receptor Protein-Tyrosine Kinases Tumor Microenvironment |
Title | Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses |
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