Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma
Abstract Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to m...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | HemaSphere |
| Online Access: | https://doi.org/10.1002/hem3.70047 |
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| author | Zoltán Kellermayer Sabrin Tahri Madelon M. E. deJong Natalie Papazian Cathelijne Fokkema Elodie C. G. Stoetman Remco Hoogenboezem Gregory vanBeek Mathijs A. Sanders Louis Boon Chelsea Den Hollander Annemiek Broijl Pieter Sonneveld Tom Cupedo |
| author_facet | Zoltán Kellermayer Sabrin Tahri Madelon M. E. deJong Natalie Papazian Cathelijne Fokkema Elodie C. G. Stoetman Remco Hoogenboezem Gregory vanBeek Mathijs A. Sanders Louis Boon Chelsea Den Hollander Annemiek Broijl Pieter Sonneveld Tom Cupedo |
| author_sort | Zoltán Kellermayer |
| collection | DOAJ |
| description | Abstract Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single‐cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single‐cell RNA‐sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control. |
| format | Article |
| id | doaj-art-8288d63a3ca04376a722d2fd5fde73f6 |
| institution | Kabale University |
| issn | 2572-9241 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj-art-8288d63a3ca04376a722d2fd5fde73f62025-01-07T12:35:28ZengWileyHemaSphere2572-92412024-12-01812n/an/a10.1002/hem3.70047Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myelomaZoltán Kellermayer0Sabrin Tahri1Madelon M. E. deJong2Natalie Papazian3Cathelijne Fokkema4Elodie C. G. Stoetman5Remco Hoogenboezem6Gregory vanBeek7Mathijs A. Sanders8Louis Boon9Chelsea Den Hollander10Annemiek Broijl11Pieter Sonneveld12Tom Cupedo13Department of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsJJP Biologics Warsaw PolandDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsDepartment of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The NetherlandsAbstract Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single‐cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single‐cell RNA‐sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.https://doi.org/10.1002/hem3.70047 |
| spellingShingle | Zoltán Kellermayer Sabrin Tahri Madelon M. E. deJong Natalie Papazian Cathelijne Fokkema Elodie C. G. Stoetman Remco Hoogenboezem Gregory vanBeek Mathijs A. Sanders Louis Boon Chelsea Den Hollander Annemiek Broijl Pieter Sonneveld Tom Cupedo Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma HemaSphere |
| title | Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma |
| title_full | Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma |
| title_fullStr | Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma |
| title_full_unstemmed | Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma |
| title_short | Interferon gamma‐mediated prevention of tumor progression in a mouse model of multiple myeloma |
| title_sort | interferon gamma mediated prevention of tumor progression in a mouse model of multiple myeloma |
| url | https://doi.org/10.1002/hem3.70047 |
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