Immune involvement of the contralateral hemisphere in a glioblastoma mouse model
Background Glioblastoma (GBM) is the most common and deadliest form of brain cancer in adults. Standard treatment, consisting of surgery and radiochemotherapy, only provides a modest survival benefit and is incapable of combating infiltrating GBM cells in other parts of the brain. New therapies in c...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000323.full |
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| author | Matheus H W Crommentuijn Sjoerd T T Schetters Sophie A Dusoswa Laura J W Kruijssen Juan J Garcia-Vallejo Yvette van Kooyk |
| author_facet | Matheus H W Crommentuijn Sjoerd T T Schetters Sophie A Dusoswa Laura J W Kruijssen Juan J Garcia-Vallejo Yvette van Kooyk |
| author_sort | Matheus H W Crommentuijn |
| collection | DOAJ |
| description | Background Glioblastoma (GBM) is the most common and deadliest form of brain cancer in adults. Standard treatment, consisting of surgery and radiochemotherapy, only provides a modest survival benefit and is incapable of combating infiltrating GBM cells in other parts of the brain. New therapies in clinical trials, such as anti-programmed cell death 1 immunotherapy, have so far shown limited success in GBM. Moreover, it is unclear how the growth of GBM suppresses the immune system locally at the site of the brain tumor or if distant sites of tumor cell migration are also involved. Invasive GBM cells in brain tissue beyond the primary tumor limit the use of surgery, thus immunotherapy could be beneficial if activated/suppressed immune cells are present in the contralateral hemisphere.Methods Here, we used a syngeneic orthotopic GL26 GBM mouse model and multiparameter fluorescence-activated cell sorting analysis to study the phenotype of resident and infiltrating immune cells in both the brain tumor hemisphere and contralateral hemisphere.Results We show that lymphoid cells, including tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) are present in the tumor and are characterized by a tolerogenic phenotype based on high immune checkpoint expression. Massive infiltration of myeloid cells is observed, expressing immune checkpoint ligands, suggesting an immune-dependent coinhibitory axis limiting TIL responses. Surprisingly, these phenotypes are paralleled in the contralateral hemisphere, showing that infiltrating immune cells are also present at distant sites, expressing key immune checkpoints and immune checkpoint ligands.Conclusion Whole-brain analysis indicates active immune involvement throughout the brain, both at the site of the primary tumor and in the contralateral hemisphere. Using the right combination and timing, immune checkpoint blockade could have the potential to activate immune cells at the site of the brain tumor and at distant sites, thereby also targeting diffusely infiltrating GBM cells. |
| format | Article |
| id | doaj-art-bbaf4c24078b4d02844263728c9e3920 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-bbaf4c24078b4d02844263728c9e39202024-11-09T09:45:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000323Immune involvement of the contralateral hemisphere in a glioblastoma mouse modelMatheus H W Crommentuijn0Sjoerd T T Schetters1Sophie A Dusoswa2Laura J W Kruijssen3Juan J Garcia-Vallejo4Yvette van Kooyk51 Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands1 Molecular Cell Biology and Immunology, Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC - Location VUMC, Amsterdam, The NetherlandsDepartment of Molecular Cell Biology and Immunology, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsBackground Glioblastoma (GBM) is the most common and deadliest form of brain cancer in adults. Standard treatment, consisting of surgery and radiochemotherapy, only provides a modest survival benefit and is incapable of combating infiltrating GBM cells in other parts of the brain. New therapies in clinical trials, such as anti-programmed cell death 1 immunotherapy, have so far shown limited success in GBM. Moreover, it is unclear how the growth of GBM suppresses the immune system locally at the site of the brain tumor or if distant sites of tumor cell migration are also involved. Invasive GBM cells in brain tissue beyond the primary tumor limit the use of surgery, thus immunotherapy could be beneficial if activated/suppressed immune cells are present in the contralateral hemisphere.Methods Here, we used a syngeneic orthotopic GL26 GBM mouse model and multiparameter fluorescence-activated cell sorting analysis to study the phenotype of resident and infiltrating immune cells in both the brain tumor hemisphere and contralateral hemisphere.Results We show that lymphoid cells, including tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) are present in the tumor and are characterized by a tolerogenic phenotype based on high immune checkpoint expression. Massive infiltration of myeloid cells is observed, expressing immune checkpoint ligands, suggesting an immune-dependent coinhibitory axis limiting TIL responses. Surprisingly, these phenotypes are paralleled in the contralateral hemisphere, showing that infiltrating immune cells are also present at distant sites, expressing key immune checkpoints and immune checkpoint ligands.Conclusion Whole-brain analysis indicates active immune involvement throughout the brain, both at the site of the primary tumor and in the contralateral hemisphere. Using the right combination and timing, immune checkpoint blockade could have the potential to activate immune cells at the site of the brain tumor and at distant sites, thereby also targeting diffusely infiltrating GBM cells.https://jitc.bmj.com/content/8/1/e000323.full |
| spellingShingle | Matheus H W Crommentuijn Sjoerd T T Schetters Sophie A Dusoswa Laura J W Kruijssen Juan J Garcia-Vallejo Yvette van Kooyk Immune involvement of the contralateral hemisphere in a glioblastoma mouse model Journal for ImmunoTherapy of Cancer |
| title | Immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| title_full | Immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| title_fullStr | Immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| title_full_unstemmed | Immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| title_short | Immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| title_sort | immune involvement of the contralateral hemisphere in a glioblastoma mouse model |
| url | https://jitc.bmj.com/content/8/1/e000323.full |
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