ENPP1是抗癌cGAMP-STING通路的先天免疫检查点
Songnan Wang1,2,3, Volker Böhnert1,2, Alby J Joseph1,2,3
1Department of Biochemistry, Stanford University, Stanford 94305, USA.
bioRxiv : the preprint server for biology
|June 19, 2023
概括
抑制ENPP1酶可以通过恢复cGAMP-STING通路和细胞外腺信号传递来增强抗瘤免疫力. 这种方法对乳腺癌治疗有希望,并与现有的免疫疗法协同作用.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- ENPP1的表达与各种癌症的预后不佳有关.
- ENPP1通过细胞外循环氨酸单酸盐 (cGAMP) 的水解,这是抗癌STING通路的关键激活剂.
- 目前尚不完全了解ENPP1致瘤作用的精确分子和细胞机制.
研究的目的:
- 阐明ENPP1在乳腺瘤生长,转移和瘤微环境 (TME) 中的作用.
- 研究ENPP1抑制对抗瘤免疫和细胞外腺素信号传递的影响.
- 评估针对乳腺癌中ENPP1的cGAMP化酶活性的治疗潜力.
主要方法:
- 单细胞RNA测序 (scRNA-seq) 用于分析ENPP1表达及其对TME的影响.
- 在癌症模型中对ENPP1的功能丧失研究.
- 选择性抑制ENPP1的cGAMP水解活性.
- 分析患者数据,将ENPP1表达与免疫透和治疗反应相关联.
主要成果:
- 过度表达ENPP1通过抑制cGAMP-STING免疫力和增强免疫抑制腺素信号,促进乳腺瘤生长和转移.
- 在TME内,ENPP1在癌细胞,层状细胞和免疫细胞中表达,抑制对cGAMP的反应.
- 损失ENPP1功能显著抑制瘤启动,生长和转移以cGAMP和STING依赖的方式.
- 选择性抑制ENPP1的cGAMP化酶活性模仿完全淘汰,恢复抗癌STING信号.
结论:
- 向ENPP1的cGAMP酶活性是通过重新激活先天的抗瘤免疫力来治疗乳腺癌的一个有前途的治疗策略.
- 患者的低ENPP1表达与增加的免疫透和对PARP抑制剂和抗PD1等免疫疗法的更好反应相关.
- 选择性ENPP1抑制减轻了先天的免疫检查点,增强了癌症免疫力,并可能与其他癌症免疫疗法协同作用.
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