Kellermayer Zoltán, Tahri Sabrin, de Jong Madelon M E, Papazian Natalie, Fokkema Cathelijne, Stoetman Elodie C G, Hoogenboezem Remco, van Beek Gregory, Sanders Mathijs A, Boon Louis, Den Hollander Chelsea, Broijl Annemiek, Sonneveld Pieter, Cupedo Tom
Department of Hematology, Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam The Netherlands.
JJP Biologics Warsaw Poland.
Hemasphere. 2024 Dec 2;8(12):e70047. doi: 10.1002/hem3.70047. eCollection 2024 Dec.
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.
多发性骨髓瘤患者的恶性浆细胞存在于骨髓中，并持续与局部免疫细胞相互作用。疾病进展和治疗反应受这种免疫环境的影响，这突出表明需要详细了解对恶性浆细胞的内源性免疫反应。在此，我们使用多发性骨髓瘤的5TGM1小鼠移植模型来剖析对骨髓瘤细胞的早期免疫反应。我们分别将5TGM1小鼠骨髓瘤细胞移植到C57Bl/6小鼠和KaLwRij小鼠中，建立稳定和进展性疾病模型。我们使用流式细胞术以及单细胞和批量转录组分析来表征稳定和进展性疾病中的差异免疫反应。在C57Bl/6小鼠中移植5TGM1细胞导致一部分动物出现肿瘤负荷低的稳定疾病。稳定疾病与NK细胞、ILC1和CD8 T细胞的持续激活和扩增相关，这种反应在疾病进展时消失。免疫细胞的单细胞RNA测序以及免疫和间充质基质细胞的批量RNA测序表明，干扰素反应的激活是稳定疾病期间的核心免疫途径。实验表明，在C57Bl/6小鼠中中和IFNγ会显著增加骨髓瘤的发生和进展，证明了该途径在疾病早期控制中的重要性。总之，我们提供了一个在具有免疫活性和可基因改造的小鼠中研究对多发性骨髓瘤进展的免疫反应的框架，并强调了骨髓免疫在肿瘤控制中的重要性。
