Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets
Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.837013/full |
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| author | Zahra Abbas Zahra Abbas Courtney George Courtney George Mathew Ancliffe Mathew Ancliffe Meegan Howlett Meegan Howlett Anya C. Jones Anya C. Jones Mani Kuchibhotla Robert J. Wechsler-Reya Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby |
| author_facet | Zahra Abbas Zahra Abbas Courtney George Courtney George Mathew Ancliffe Mathew Ancliffe Meegan Howlett Meegan Howlett Anya C. Jones Anya C. Jones Mani Kuchibhotla Robert J. Wechsler-Reya Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby |
| author_sort | Zahra Abbas |
| collection | DOAJ |
| description | Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc-driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1-deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1-deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1+ macrophages, and we show that CD45high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments. |
| first_indexed | 2024-12-19T21:40:55Z |
| format | Article |
| id | doaj.art-444717f125444b249523592585e3f8d3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T21:40:55Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-444717f125444b249523592585e3f8d32022-12-21T20:04:39ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-03-011310.3389/fimmu.2022.837013837013Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy TargetsZahra Abbas0Zahra Abbas1Courtney George2Courtney George3Mathew Ancliffe4Mathew Ancliffe5Meegan Howlett6Meegan Howlett7Anya C. Jones8Anya C. Jones9Mani Kuchibhotla10Robert J. Wechsler-Reya11Nicholas G. Gottardo12Nicholas G. Gottardo13Nicholas G. Gottardo14Raelene Endersby15Raelene Endersby16Centre for Child Health Research, University of Western Australia, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaSchool of Medical and Health Sciences, Edith Cowan University, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaSchool of Veterinary and Life Sciences, Murdoch University, Perth, WA, AustraliaCentre for Child Health Research, University of Western Australia, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaCentre for Child Health Research, University of Western Australia, Perth, WA, AustraliaCancer Centre Core Research, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaNCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United StatesCentre for Child Health Research, University of Western Australia, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaDepartment of Paediatric and Adolescent Oncology and Haematology, Perth Children’s Hospital, Perth, WA, AustraliaCentre for Child Health Research, University of Western Australia, Perth, WA, AustraliaBrain Tumour Research Program, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA, AustraliaMedulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc-driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1-deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1-deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1+ macrophages, and we show that CD45high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments.https://www.frontiersin.org/articles/10.3389/fimmu.2022.837013/fullmedulloblastomaimmune microenvironmentmicrogliaimmunocharacterizationchemotherapycraniospinal irradiation |
| spellingShingle | Zahra Abbas Zahra Abbas Courtney George Courtney George Mathew Ancliffe Mathew Ancliffe Meegan Howlett Meegan Howlett Anya C. Jones Anya C. Jones Mani Kuchibhotla Robert J. Wechsler-Reya Nicholas G. Gottardo Nicholas G. Gottardo Nicholas G. Gottardo Raelene Endersby Raelene Endersby Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets Frontiers in Immunology medulloblastoma immune microenvironment microglia immunocharacterization chemotherapy craniospinal irradiation |
| title | Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets |
| title_full | Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets |
| title_fullStr | Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets |
| title_full_unstemmed | Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets |
| title_short | Conventional Therapies Deplete Brain-Infiltrating Adaptive Immune Cells in a Mouse Model of Group 3 Medulloblastoma Implicating Myeloid Cells as Favorable Immunotherapy Targets |
| title_sort | conventional therapies deplete brain infiltrating adaptive immune cells in a mouse model of group 3 medulloblastoma implicating myeloid cells as favorable immunotherapy targets |
| topic | medulloblastoma immune microenvironment microglia immunocharacterization chemotherapy craniospinal irradiation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.837013/full |
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