PO.CL12.02 · 临床研究
Galectin-9作为一种糖修饰佐剂增强Elotuzumab介导的多发性骨髓瘤免疫治疗
Galectin-9 as a glycan-modulating adjuvant to enhance Elotuzumab-mediated immunotherapy in multiple myeloma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
多发性骨髓瘤（MM）是一种以骨髓内恶性产抗体浆细胞克隆性扩增为特征的血液系统恶性肿瘤。尽管治疗策略取得进展，MM仍无法治愈，凸显出需要创新方法来增强现有免疫疗法。骨髓瘤细胞的表面糖库或糖组谱在调节宿主-肿瘤免疫相互作用中发挥关键作用，影响免疫识别和治疗反应性。Galectin-9（Gal-9）是一种β-半乳糖苷结合凝集素，通过与特定糖结构的相互作用，已成为免疫和肿瘤细胞信号传导的关键调控因子。我们实验室近期的发现揭示了Gal-9对B细胞表面糖具有强结合亲和力，导致信号淋巴细胞活化分子F7（SLAMF7）的上调——SLAMF7是恶性浆细胞上表达的关键免疫调节受体，也是单克隆抗体Elotuzumab经验证的治疗靶点。在本研究中，我们探讨了Gal-9处理是否通过调节MM细胞中SLAMF7表达和免疫反应性来增强Elotuzumab疗效。使用流式细胞术，我们在B淋巴母细胞模型和原代MM骨髓样本中定量了Gal-9结合和SLAMF7表面表达。与未处理对照相比，Gal-9暴露显著增加SLAMF7表达（约3倍）。此外，当与自然杀伤（NK）细胞在抗SLAMF7抗体Elotuzumab存在下共培养时，经Gal-9预处理的MM细胞表现出增强的抗体依赖性细胞毒性（ADCC），提示免疫介导的细胞毒性得到功能性增强（约2.5倍）。所有方法均至少进行3次，并使用学生t检验分析统计学显著性（*p≤0.05，**p≤0.01，***p≤0.001）。总的来说，这些发现凸显Gal-9作为一种有前景的组合药物，能够增强SLAMF7表达并放大Elotuzumab诱导的MM细胞毒性。本研究强调了将糖靶向策略与现有基于单克隆抗体的方案相整合以改善多发性骨髓瘤治疗疗效和患者结局的治疗潜力。
查看英文原文 English abstract
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal expansion of malignant antibody-producing plasma cells within the bone marrow. Despite advances in therapeutic strategies, MM remains incurable, emphasizing the need for innovative approaches to augment current immunotherapies. The surface glycan repertoire or glycome profile of myeloma cells plays a pivotal role in modulating host-tumor immune interactions, influencing both immune recognition and therapeutic responsiveness. Galectin-9 (Gal-9), a beta-galactoside-binding lectin, has emerged as a key regulator of immune and tumor cell signaling through its interaction with specific glycan structures. Recent findings from our laboratory revealed a strong binding affinity of Gal-9 for B cell surface glycans, resulting in the upregulation of signaling lymphocytic activation molecule F7 (SLAMF7), a critical immunoregulatory receptor expressed on malignant plasma cells and a validated therapeutic target of the monoclonal antibody Elotuzumab. In this study, we investigated whether Gal-9 treatment enhances Elotuzumab efficacy by modulating SLAMF7 expression and immune responsiveness in MM cells. Using flow cytometry, we quantified Gal-9 binding and SLAMF7 surface expression across B-lymphoblast models and primary MM bone marrow samples. Gal-9 exposure significantly increased SLAMF7 expression (~3-fold) compared to untreated controls. Furthermore, Gal-9-primed MM cells exhibited augmented antibody-dependent cellular cytotoxicity (ADCC) when co-cultured with natural killer (NK) cells in the presence of anti-SLAMF7 antibody Elotuzumab, suggesting (~2.5-fold) functional enhancement of immune-mediated cytotoxicity. All methods were conducted at least 3 times and analyzed for statistical significance using Student's t-test (*p≤0.05, **p≤0.01, *** p≤0.001). Collectively, these findings highlight Gal-9 as a promising combinatorial agent capable of enhancing SLAMF7 expression and amplifying Elotuzumab-induced cytotoxicity in MM. This study underscores the therapeutic potential of integrating glycan-targeting strategies with existing monoclonal antibody-based regimens to improve treatment efficacy and patient outcomes in multiple myeloma.
利益披露 Disclosure
R. Shil, None..
G. Koehne, None..
C. Dimitroff, None.