与人类PD1相比,动物PD1中的进化指纹赋予了减弱的活性和增强的瘤免疫力
bioRxiv : the preprint server for biology
|October 7, 2024
概括
人类PD1比小鼠PD1更具抑制性,因为相互作用更强. 动物PD1经历了功能放松,影响研究模型中的抗瘤免疫和抗PD1反应.
科学领域:
- 免疫学 免疫学 免疫学
- 进化生物学 进化生物学
- 分子生物学分子生物学
背景情况:
- 免疫检查点受体编程细胞死亡蛋白1 (PD1) 功能主要在小鼠模型中进行研究.
- 人类和小鼠的PD1蛋白仅共享59.6%的氨基酸特征,这表明了潜在的物种特异性差异.
研究的目的:
- 研究人类和小鼠PD1信号传递之间的机制差异.
- 探索这些特定物种变异的进化基础.
- 评估对抗PD1/PDL1癌症免疫疗法的影响.
主要方法:
- 人类和小鼠PD1蛋白序列和相互作用的比较分析.
- 生物化学试验测量与PDL1,PDL2和Shp2酸酶的结合亲缘关系.
- 在脊椎动物物种中对PD1的演化分析.
- 使用人性化小鼠模型进行功能性研究,以评估T细胞活性和治疗反应.
主要成果:
- 与小鼠PD1相比,人类PD1与其配体 (PDL1,PDL2) 和酸酶Shp2具有更强的抑制相互作用.
- 在人类PD1中存在一种新型的保存动机,在动物中缺席,对于增强Shp2招募至关重要.
- 进化分析表明,动物PD1的功能放松,特别是在K-Pg边界附近.
- 对小鼠PD1的人性化破坏了抗瘤T细胞的活性,并改变了抗PD1疗法的疗效.
结论:
- 在PD1通路功能方面存在显著的物种特异性差异,人类PD1更强效.
- 动物PD1已经经历了功能放松,这可能会限制其可转化到人类癌症免疫疗法.
- 了解这些进化和机理变异对于解释小鼠模型数据和改进抗PD1/PDL1疗法至关重要.
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