用Cas13d对免疫抑制基因进行多重抑制,用于结合性癌症免疫治疗
Feifei Zhang1,2,3, Ryan D Chow1,2,3,4,5, Emily He1,2,3,6
1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Nature biotechnology
|January 17, 2025
概括
通过基因沉默 (MUCIG) 进行多重通用组合免疫疗法使用CRISPR-Cas13d来沉默多个免疫抑制基因,增强抗瘤免疫力. 这种新的方法通过重塑瘤微环境,在各种瘤模型中显示出显著的有效性.
科学领域:
- 免疫学 免疫学 免疫学
- 基因治疗 基因治疗
- 癌症研究 癌症研究
背景情况:
- 免疫抑制性瘤微环境 (TME) 阻碍了有效的癌症免疫治疗.
- 多剂组合疗法对于克服TME介导的免疫抑制至关重要.
研究的目的:
- 开发一种新的基因抑制免疫疗法策略,针对TME内的多个免疫抑制基因.
- 在临床前癌症模型中,通过基因沉默 (MUCIG) 评估多重通用组合免疫疗法的疗效.
主要方法:
- 使用CRISPR-Cas13d技术对内源性免疫抑制基因 (Cd274/Pdl1,Lgals9/Galectin9,Lgals3/Galectin3和Cd47) 进行多重基因沉默.
- 通过腺相关病毒 (AAV) 传递的MUCIG载体以确定AAV-Cas13d-PGGC.
- 在综合性瘤模型中评估了抗瘤疗效,TME重塑 (CD8+ T细胞透,中性粒细胞减少) 和基因表达特征 (整个转录组概况).
- 对抗shRNA治疗和个别基因淘汰策略的MUCIG疗效进行比较.
- 研究使用高保真Cas13d (hfCas13d) 来提高安全性和有效性.
主要成果:
- 在多种综原性瘤模型中,AAV-Cas13d-PGGC显示出显著的抗瘤疗效.
- MUCIG成功地重塑了TME,其特点是CD8+ T细胞透率增加和中性粒细胞数量减少.
- 整个转录基因组分析证实了在目标基因上进行敲除,并且对目标基因产生了最小的非目标影响.
- AAV-Cas13d-PGGC的表现优于shRNA和单基因沉默方法.
- 使用hfCas13d优化的MUCIG在体内显示出强大的有效性,而不会引起体重减轻或肝毒性.
结论:
- MUCIG是一个多功能和可编程的平台,用于在体内沉默多个免疫相关基因.
- 这种方法有效地重塑了免疫抑制的TME,并增强了抗瘤免疫力.
- 在不同类型的癌症中,MUCIG具有广泛的治疗应用的前景.
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