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向IL-33重新编程瘤微环境,并增强抗瘤反应对抗PD-L1免疫疗法的反应

Yanyang Nan¹, Yu Bai¹, Xiaozhi Hu¹

¹Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, China.

Journal for immunotherapy of cancer

|September 4, 2024

概括

阻断IL-33/ST2信号通过减少免疫抑制细胞和增加T细胞反应来增强抗PD-L1癌症治疗. 双重向IL-33和PD-L1显示出优异的抗瘤疗效和长期免疫力.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
分子医学是分子医学.

背景情况:

免疫抑制性瘤微环境 (TME) 限制了免疫检查点抑制剂的有效性,如抗PD-L1.
IL-33/ST2信号通路在TME中起着关键作用,但其对抗PD-L1疗法的影响尚未完全理解.

研究的目的:

调查IL-33/ST2信号传递在抗PD-L1治疗期间免疫抑制性TME中的作用.
评估阻断IL-33/ST2信号传递,单独或与抗PD-L1结合,用于癌症治疗的治疗潜力.

主要方法:

利用RNA-seq,ELISA,Western Blot (WB) 和免疫光 (IF) 来分析易斯肺癌模型中的分子机制.
开发了一种针对IL-33的sST2-Fc融合蛋白,并在结肠和肺瘤模型中测试了其与抗PD-L1结合的疗效.
产生双功能融合蛋白质,同时准IL-33和PD-L1,并通过RNA-seq,scRNA-seq,FACS,IF和WB评估底层机制.

主要成果:

抗PD-L1治疗导致瘤透的ST2+调节性T细胞 (Tregs) 的增加.
通过sST2-Fc阻断IL-33/ST2信号传递,通过促进T细胞反应,增强了抗PD-L1的抗瘤疗效.
一种双功能抗PD-L1-sST2融合蛋白显示出优异的抗瘤活性,减少了免疫抑制细胞 (Tregs,耗尽的CD8+T细胞) 和增加了细胞毒性T淋巴细胞,导致瘤抑制和延长生存时间.

结论:

IL-33/ST2信号传递有助于在PD-L1抗体治疗期间观察到的免疫抑制.
通过sST2-Fc或双向融合蛋白阻止IL-33/ST2信号传递,有效地重塑TME并诱导强大的抗瘤效应.
同时准IL-33和PD-L1代表了癌症治疗的有前途的治疗策略.

关键词:

免疫检查点抑制剂免疫检查点抑制剂免疫调节器免疫调节器免疫治疗是一种免疫疗法.一个T调节单元 - - Treg调节单元瘤微环境 - - 瘤微环境

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