PD-1阻塞以性别和年龄依赖的方式调节骨重塑
Gwenyth J Joseph1,2, Lawrence A Vecchi2,3, Sasidhar Uppuganti2,3
1Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232.
概括
免疫检查点抑制剂 (ICI) 通过扩大骨髓中的T细胞引起骨质损失. 缺乏T细胞可以防止这种骨损失,在ICI治疗期间识别患有骨折风险的患者.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 骨生物学 骨生物学 骨生物学
背景情况:
- 免疫检查点抑制剂 (ICI) 改善癌症存活率,但会导致与免疫相关的不良事件 (irAEs).
- ICI对骨代谢和骨折风险的影响尚不清楚,临床前数据相互矛盾.
- 之前的研究没有检查ICI对雌性,老年小鼠或骨折风险的影响.
研究的目的:
- 在临床前模型中研究编程细胞死亡蛋白1 (PD-1) 阻断对骨质,强度和骨折风险的影响.
- 为了确定T细胞在ICI诱导的骨损失中的作用.
- 在接受ICI治疗的患者中确定骨折风险的潜在生物标志物.
主要方法:
- 在雄性和雌性小鼠中PD-1的全球删除.
- 使用α-PD-1抗体进行药理性PD-1阻断.
- 评估骨质量,骨强度和骨质细胞活性.
- 对骨髓T细胞种群的分析.
- 在T细胞缺乏小鼠的研究.
主要成果:
- 全球PD-1缺失导致成熟小鼠的骨质损失,在青少年中产生性差异的影响.
- 服用α-PD-1可降低骨质量,增加骨质细胞活性,并在骨髓中扩大T细胞子集.
- 缺乏T细胞的小鼠受到α-PD-1诱导的骨损失的保护.
- 在成年男性和年轻女性中观察到骨强度下降.
结论:
- PD-1 阻塞会导致骨质损失,骨髓中的 T 细胞介导这种损失.
- 骨髓中的T细胞扩张是ICI诱导的骨损失的关键机制.
- 在骨髓中提升T细胞的作用可能会在ICI治疗期间识别患有骨折风险较高的患者.
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