用于治疗 B 细胞急性淋巴细胞白血病的患者衍生异种移植小鼠 CD40 激动剂

IF 12.7 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

ACS Central Science Pub Date : 2024-11-14 DOI:10.1158/1078-0432.ccr-24-1391

Pierre-Simon Bellaye, Aleksandra Georgievski, Paola Ballerini, Boutheina Bouslama, Corentin Richard, Romain Boidot, Guillaume Chevreux, Véronique Legros, Julien Guy, Jessica Racine, Bertrand Collin, Carmen Garrido, Ronan Quéré

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引用次数: 0

摘要

目的：分化簇 40（CD40）在 B 细胞急性淋巴细胞白血病（B-ALL）病例中表达。然而，CD40 激活对 B-ALL 细胞的影响从未在体内进行过测试。实验设计：我们临床前研究的目的是利用患者异种移植（PDX）小鼠模型研究 CD40 激动剂治疗 B-ALL 的潜力。研究结果静脉注射CD40激动剂可显著抑制体内B-ALL细胞的增殖和生长，同时迅速激活细胞外信号调节激酶（ERK）通路，从而诱导细胞凋亡并破坏细胞周期的进展。与ERK特异性抑制剂联合处理进一步证明，CD40刺激以ERK依赖性方式诱导B-ALL细胞促凋亡。蛋白质组分析揭示了与 B-ALL 扩增和维持相关的关键信号通路的改变。此外，CD40激动剂明显降低了PDX小鼠中白血病启动细胞的频率和白血病的发展。我们的研究表明，CD40 激动剂可与长春新碱和地塞米松等化疗药物联合使用，而且这种联合用药显示出更好的疗效。此外，CD40激动剂对表达CD40的前B-ALL（EGIL B-III）比对缺乏CD40表达的普通B-ALL（EGIL B-II）更有效。结论这些研究结果表明，CD40激动剂是治疗小儿B-ALL的有前途的免疫治疗候选药物，值得进一步临床研究，以改善表达CD40的B-ALL患者的预后。

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CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia

Purpose: Cluster of differentiation 40 (CD40) is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases. However, the effect of CD40 activation on B-ALL cells has never been tested in vivo. Experimental Design: The aim of our preclinical study was to investigate the therapeutic potential of a CD40 agonist in the treatment of B-ALL using patient-derived xenograft (PDX) mouse models. Results: Intravenous administration of the CD40 agonist significantly impeded B-ALL cell proliferation and growth in vivo, accompanied by rapid activation of the extracellular signal-regulated kinase (ERK) pathway, leading to the induction of apoptosis and disruption of cell cycle progression. Co-treatment with a specific inhibitor of ERK further demonstrated that CD40 stimulation induced the pro-apoptosis of B-ALL cells in an ERK-dependent manner. Proteomic analysis revealed alterations in key signaling pathways associated with B-ALL expansion and maintenance. Moreover, the CD40 agonist markedly reduced the frequency of leukemia-initiating cells and leukemia development in PDX mice. Our study showed that the CD40 agonist can be associated with chemotherapeutic agents such as vincristine and dexamethasone, and this combination showed improved effectiveness. Additionally, the CD40 agonist was more effective on pre-B-ALL (EGIL B-III) that expressed CD40, than on common B-ALL (EGIL B-II) that lacked CD40 expression. Conclusion: These findings suggest that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL, warranting further clinical investigations to improve patient outcomes in CD40-expressing B-ALL.

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来源期刊

ACS Central Science Chemical Engineering-General Chemical Engineering

CiteScore

25.50

自引率

0.50%

发文量

194

审稿时长

10 weeks

期刊介绍： ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.