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BTLA-HVEM轴限制了CAR T细胞在癌症中的疗效

Puneeth Guruprasad^1,2,3,4, Alberto Carturan^2,3,4, Yunlin Zhang^2,3,4

¹Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.

Nature immunology

|June 3, 2024

概括

在仿真抗原受体 (CAR) T 细胞中删除BTLA可以改善瘤控制. 这种T细胞免疫治疗策略通过阻断BTLA-HVEM检查点来克服免疫抑制,增强CAR T细胞功能.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
免疫治疗是一种免疫疗法.

背景情况:

基于T细胞的免疫疗法面临来自免疫抑制瘤微环境的挑战.
在T细胞上的BTLA和调节性T细胞上的HVEM之间的相互作用是关键的免疫抑制机制.

研究的目的:

调查BTLA-HVEM轴在CAR T细胞治疗疗效中的作用.
为了确定在CAR T细胞中删除BTLA是否可以改善抗瘤反应.

主要方法:

在患者的CAR T细胞中分析BTLA表达.
在CAR T细胞中BTLA的遗传删除.
在临床前模型中评估瘤控制和CAR T细胞持久性.
通过SHP-1/SHP-2酸酶对BTLA中介抑制的机制研究.

主要成果:

在CAR T细胞上高BTLA表达与不良的临床结果相关.
在CAR T细胞中BTLA淘汰导致淋巴瘤和固体瘤模型中的瘤控制和持久性增强.
BTLA与HVEM的接触通过招募SHP-1和SHP-2酸酶来抑制CAR-T细胞,从而损害CAR信号传递.

结论:

BTLA-HVEM轴代表了一个关键的免疫检查点,限制了CAR T细胞免疫疗法的有效性.
通过在CAR-T细胞中删除BTLA来向BTLA-HVEM相互作用是改善癌症治疗的有希望的策略.

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