Myeloma Lymphoma Research Group, Champalimaud Experimental Clinical Research Programme, Champalimaud Foundation, Lisbon, Portugal.
Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Front Immunol. 2022 Jul 7;13:909880. doi: 10.3389/fimmu.2022.909880. eCollection 2022.
Multiple myeloma (MM), the third most frequent hematological cancer worldwide, is characterized by the proliferation of neoplastic plasma cells in the bone marrow (BM). One of the hallmarks of MM is a permissive BM microenvironment. Increasing evidence suggests that cell-to-cell communication between myeloma and immune cells tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line, MOPC315.BM, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as granzyme B and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.
多发性骨髓瘤（MM）是全球第三大常见的血液系统恶性肿瘤，其特征是骨髓（BM）中恶性浆细胞的增殖。MM 的一个标志是允许的 BM 微环境。越来越多的证据表明，骨髓瘤和免疫细胞之间的细胞间通讯——肿瘤细胞衍生的细胞外囊泡（EV）——在 MM 的发病机制中起着关键作用。因此，我们旨在探索 MM 衍生 EV 诱导的 BM 免疫改变。为此，我们用骨髓瘤细胞系 MOPC315.BM 接种免疫功能正常的 BALB/cByJ 小鼠，诱导 MM 表型。在肿瘤建立后，对 BM 微环境的特征分析显示，淋巴细胞表达了激活和抑制标志物，分别为颗粒酶 B 和 PD-1。此外，在移植 MOPC315.BM 肿瘤细胞之前，用 MOPC315.BM 衍生的 EV 对动物进行预处理并没有预料到疾病表型。然而，它诱导了 BM 环境中的抑制特征，例如 CD4+T 细胞中 PD-1 表达的增加。总的来说，我们的研究结果揭示了 MOPC315.BM 衍生 EV 蛋白含量作为免疫生态位重塑的促进剂的参与，这加强了评估 MM 可能影响免疫微环境的机制的重要性。
