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对抗PD-1和抗LAG-3检查点封锁的反应与调控性T细胞重编程有关
Annah S Rolig1, Xiyu Peng2, Elizabeth R Sturgill1
1Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR 97213, USA.
Science translational medicine
|April 9, 2025
概括
高频率的LAG-3+淋巴细胞预测抗PD-1治疗的耐药性. 与抗PD-1和抗LAG-3的联合治疗显示出有效性,与抗药性瘤中调节性T细胞可塑性有关.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 癌症治疗方法 癌症治疗方法
背景情况:
- 免疫检查点阻塞 (ICB) 与抗PD-1 (aPD-1) 疗法一样,已经改变了癌症治疗,但面临治疗耐药性的挑战.
- 一个先前识别的高频率LAG-3+淋巴细胞在周围血液中的生物标志物预测了对aPD-1治疗的耐药性.
研究的目的:
- 通过模仿人类生物标志物的小鼠模型,研究aPD-1耐药性背后的机制.
- 在耐药模型中评估与抗PD-1和抗LAG-3 (aLAG-3) 联合治疗的疗效.
- 探索调节性T细胞 (Tregs) 对组合疗法的反应中的作用.
主要方法:
- 鉴定和描述具有高 (LAG-3hi) 或低 (LAG-3lo) LAG-3+淋巴细胞频率的小鼠瘤模型.
- 在这些模型中评估aPD-1和aPD-1+aLAG-3疗法的疗效,包括CD8+和CD4+T细胞枯竭研究.
- 使用记者小鼠 (Foxp3 × ROSA YFP) 分析Treg表型可塑性和不稳定的Treg种群.
- 在患有转移性黑色素瘤的患者队列中,Treg可塑性与治疗反应的相关性.
主要成果:
- 在LAG-3hi小鼠模型中,重复了在患者中观察到的aPD-1耐药性.
- 联合aPD-1 + aLAG-3疗法在LAG-3hi小鼠中显示出有效性,依赖于CD8+ T细胞.
- 在LAG-3hi小鼠中,CD4+ T细胞枯竭增强了组合治疗的疗效.
- 增加的不稳定的Treg种群与小鼠和患者对组合治疗的反应改善相关.
结论:
- 在对aPD-1 + aLAG-3组合疗法的反应中,Treg表型可塑性起着至关重要的作用.
- 不稳定的Tregs可以作为组合治疗疗效的预测生物标志物.
- 准Treg可塑性可能为PD-1-耐火性癌症患者提供治疗策略.
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