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DGKα/ζ抑制剂与PD-1检查点疗法相结合,促进T细胞介导的抗瘤免疫力

Michael Wichroski¹, Joseph Benci², Si-Qi Liu¹

¹Research and Development, Bristol Myers Squibb Company, Cambridge, MA 02142, USA.

Science translational medicine

|October 25, 2023

概括

下一代癌症治疗涉及二重抑制二甲基酶α/zeta (DGKα/ζ),以增强对抗抗PD-1阻塞的瘤的T细胞反应.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物化学生物化学

背景情况:

编程细胞死亡蛋白1 (PD-1) 免疫检查点阻塞疗法已经改变了癌症治疗,但面临阻力.
下一代策略对于克服对PD-1封锁的原发性和获得性抵抗至关重要.

研究的目的:

识别能够增强T细胞激活并补充PD-1阻断的小分子.
探索癌症免疫治疗的新型细胞内T细胞检查点.

主要方法:

人类初级T细胞的高通量查,以识别小分子调节器.
使用基于脂质的光亲和探针进行化学蛋白质定型,用于目标识别.
使用小鼠瘤模型进行体外和体内研究以评估治疗疗效.

主要成果:

确定了一种新型化学序列,可以抑制二甲基甘油激酶α和 ζ (DGKα/ζ).
抑制DGKα/ζ增强了T细胞受体信号,克服了对PD-1封锁的抵抗机制.
双重DGKα/ζ抑制与αPD-1治疗相结合,在临床前模型中显示出强大的瘤回归.

结论:

向DGKα/ζ代表了一个有希望的下一代战略,以增强T细胞介导的癌症免疫疗法.
双重DGKα/ζ抑制可以通过增强T细胞激活来克服对PD-1阻塞的抵抗.
这种方法扩大了检查点阻塞治疗在癌症治疗中的潜力.

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