School of Biomolecular & Biomedical Science, University College Dublin (UCD), Dublin 4, Ireland.
Conway Institute of Biomolecular and Biomedical Research, University College Dublin (UCD), Dublin 4, Ireland.
Cells. 2022 Oct 25;11(21):3365. doi: 10.3390/cells11213365.
Daratumumab (DARA) has improved the outcome of treatment of multiple myeloma (MM). DARA acts via complement-dependent and -independent mechanisms. Resistance to DARA may result from upregulation of the complement inhibitory proteins CD55 and CD59, downregulation of the DARA target CD38 on myeloma cells or altered expression of the checkpoint inhibitor ligand programmed death ligand-1 (PD-L1) or other mechanisms. In this study, EVs were isolated from peripheral blood (PB) and bone marrow (BM) from multiple myeloma (MM) patients treated with DARA and PB of healthy controls. EV size and number and the expression of CD38, CD55, CD59 and PD-L1 as well as the EV markers CD9, CD63, CD81, CD147 were determined by flow cytometry. Results reveal that all patient EV samples express CD38, PD-L1, CD55 and CD59. The level of CD55 and CD59 are elevated on MM PB EVs compared with healthy controls, and the level of PD-L1 on MM PB EVs is higher in patients responding to treatment with DARA. CD147, a marker of various aspects of malignant behaviour of cancer cells and a potential target for therapy, was significantly elevated on MM EVs compared with healthy controls. Furthermore, mass spectrometry data suggests that MM PB EVs bind DARA. This study reveals a MM PB and BM EV protein signature that may have diagnostic and prognostic value.
达雷妥尤单抗（DARA）改善了多发性骨髓瘤（MM）的治疗效果。DARA 通过补体依赖性和非依赖性机制发挥作用。对 DARA 的耐药性可能是由于骨髓瘤细胞上补体抑制蛋白 CD55 和 CD59 的上调、DARA 靶标 CD38 的下调或检查点抑制剂配体程序性死亡配体-1（PD-L1）或其他机制的改变表达。在这项研究中，从接受 DARA 治疗的多发性骨髓瘤（MM）患者的外周血（PB）和骨髓（BM）以及健康对照者的 PB 中分离出 EVs。通过流式细胞术测定 EV 的大小和数量以及 CD38、CD55、CD59 和 PD-L1 的表达以及 EV 标志物 CD9、CD63、CD81、CD147。结果表明，所有患者的 EV 样本均表达 CD38、PD-L1、CD55 和 CD59。与健康对照者相比，MM PB EVs 上的 CD55 和 CD59 水平升高，而对 DARA 治疗有反应的患者的 MM PB EVs 上的 PD-L1 水平更高。CD147 是癌细胞恶性行为各个方面的标志物，也是潜在的治疗靶点，在 MM EVs 上的水平明显高于健康对照者。此外，质谱数据表明 MM PB EVs 结合 DARA。这项研究揭示了 MM PB 和 BM EV 蛋白特征，可能具有诊断和预后价值。
