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设计用于释放干扰素β和scFv-PD1的全源干细胞向质母细胞瘤并改变瘤微环境

Ioulia Vogiatzi¹, Lucia Moreno Lama², Amelia Lehmann²

¹Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.

|June 9, 2024

概括

这项研究设计了介质细胞干细胞 (MSC) 来对抗质母细胞瘤 (GBM). 这些修改后的MSC提供免疫调节疗法,增强T细胞反应并降低瘤细胞活力,以改善GBM治疗.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
生物技术是生物技术.

背景情况:

质母细胞瘤 (GBM) 是高度恶性的脑瘤,具有抑制免疫力的特性,阻碍有效的免疫疗法.
目前针对GBM的免疫治疗策略由于瘤微环境的抵抗性而面临局限性.

研究的目的:

设计介质干细胞 (MSCs) 来表达双重功能治疗剂,以对抗GBM.
评估这些工程MSCs在诱导瘤细胞亡,增强抗瘤免疫力和调节瘤微环境方面的有效性.

主要方法:

利用CRISPR/Cas9技术创建干扰素受体1淘汰MSCs (MSC^KO) 工程设计以分泌干扰素β (IFNβ).
进一步修改了MSC以表达单链可变片段 (scFv),针对编程死亡-1 (PD-1).
在MSC中同时表达IFNβ和scFv-PD1 (MSC^KO-IFNβ-scFv-PD1),并在体外和临床前的GBM模型中使用合成细胞外基质 (sECM) 封装评估了它们的效果.

主要成果:

工程MSC^KO-IFNβ在GBM细胞中诱导了亡,并上调了PD-L1表达.
MSC^KO-scFv-PD1增强了T细胞激活和瘤细胞杀死.
在MSC^KO-IFNβ-scFv-PD1中IFNβ和scFv-PD1的同时表达导致T细胞激活,并在体外减少瘤细胞活力.
用sECM封装的MSC^KO-IFNβ-scFv-PD1治疗增加了CD4+,CD8+T细胞,成熟的树突细胞,并在切除的瘤中激活了微质.

结论:

发射IFNβ和PD-1阻断剂的工程MSC显示出强大的抗瘤活性对抗GBM.
这些修改后的MSC有效地重塑了免疫抑制性瘤微环境,促进了促炎和抗瘤免疫反应.
开发的基于MSC的免疫疗法具有显著的潜力,可以提高质母细胞瘤治疗的治疗结果.

关键词:

如果IFNββ 检查点抑制剂检查点抑制剂质母细胞瘤是什么免疫调节免疫调节免疫调节切除切除切除切除 scFv-PD1 的使用情况.

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