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针对骨髓细胞的免疫疗法克服了免疫逃避性神经母细胞瘤的抑制障碍

Marie Ménard^1,2, Hiroyuki Yoda^1,2, Nicole Nasholm^1,3

¹Department of Neurology, University of California, San Francisco, CA, USA.

The Journal of experimental medicine

|July 14, 2025

概括

一种神经母细胞瘤 (Mycn-nGEMM) 的新型小鼠模型显示,将PD-L1向巨细胞,而不是瘤细胞,可以克服免疫逃避. 将抗PD-L1与CD40激动剂结合起来,对治疗高危神经母细胞瘤有很大的希望.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
遗传学是一个遗传学.

背景情况:

神经母细胞瘤是具有不良预后的侵袭性儿科癌症,特别是具有MYCN放大特征的高风险形式.
这些瘤往往表现出一种免疫逃避的微环境,其特点是丰富的免疫抑制性巨细胞.
现有的高风险神经母细胞瘤治疗方法的疗效有限,需要新的治疗策略.

研究的目的:

开发和描述一种基因工程小鼠模型 (Mycn-nGEMM),该模型总结了人类高风险神经母细胞瘤的关键特征.
在这个模型中研究免疫检查点抑制剂的疗效,并阐明它们的作用机制.
探索组合疗法,以克服神经母细胞瘤中的免疫逃避.

主要方法:

一种可移植的,非生殖系,基因工程小鼠模型 (Mycn-nGEMM) 的生成,由Mycn.
用抗PD-L1,抗PD-1和抗CTLA-4抗体单独或与CD40激动剂结合治疗携带瘤的Mycn-nGEMM小鼠.
分析瘤微环境的变化,包括免疫细胞透和细胞因子表达,使用流细胞计和免疫组织化学.
鉴定癌细胞分泌的诱导巨细胞PD-L1表达的因素.

主要成果:

Mycn-nGEMM模型成功地复制了人类MYCN增强神经母细胞瘤的免疫逃避性,丰富巨细胞的瘤微环境.
抗PD-L1疗法显著抑制瘤生长,并通过减少免疫抑制性巨细胞和增加T细胞透来重塑瘤微环境.
瘤细胞表达了低水平的PD-L1,而抗炎性巨细胞在小鼠和人类神经母细胞瘤中表达了高水平的PD-L1.
由Mycn-nGEMM癌细胞分泌的细胞因子,如巨细胞迁移抑制因子,被发现可以驱动巨细胞的PD-L1表达.
与抗PD-L1和CD40激动剂的联合治疗导致Mycn-nGEMM小鼠的生存率提高.

结论:

Mycn-nGEMM小鼠模型是研究神经母细胞瘤中免疫逃避的一个有价值的工具.
将PD-L1向与瘤相关的巨细胞,而不是瘤细胞,是神经母细胞瘤免疫疗法的有希望的策略.
针对骨髓细胞的免疫疗法,可能与其他药物 (如CD40激动剂) 结合使用,对于克服高风险神经母细胞瘤的免疫逃避具有显著的潜力.

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