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一个小分子抑制剂的PTP1B和PTPN2增强T细胞抗瘤免疫力

Shuwei Liang^1,2, Eric Tran³, Xin Du^1,2

¹Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.

Nature communications

|July 27, 2023

概括

一种新的小分子抑制剂,Compound-182,通过向PTP1B和PTPN2,有效地增强T细胞抗瘤免疫力. 这种方法增强了瘤抑制和免疫治疗的敏感性.

科学领域:

免疫学免疫学免疫学
药理学药理学是指药理学的学科.
在瘤学瘤学.

背景情况:

蛋白氨酸酸酶1B (PTP1B) 和N2 (PTPN2) 是T细胞功能的关键调节者.
抑制PTP1B和PTPN2是增强抗瘤免疫力的有希望的策略.
现有的PTP1B/PTPN2抑制剂正在研究用于固体瘤治疗.

研究的目的:

评估一种新的小分子抑制剂Compound-182的治疗潜力,该药物向PTP1B和PTPN2.
在临床前模型中评估Compound-182对T细胞介导的抗瘤免疫力和瘤生长的影响.
为了确定Compound-182是否可以克服对现有的癌症免疫疗法的抗性.

主要方法:

化合物-182被描述为一种强效和选择性的活性位点竞争性抑制剂,抑制PTP1B和PTPN2.
在小鼠模型中评估了Compound-182对T细胞招募,激活和瘤生长的影响.
瘤对单独使用Compound-182和与α-PD-1疗法结合治疗的反应,在免疫性和感冒性瘤中均被评估.

主要成果:

化合物-182显示出强大的PTP1B和PTPN2抑制,增强T细胞的招募和激活.
用Compound-182治疗抑制了小鼠的瘤生长,没有显著的免疫相关毒性.
化合物-182在免疫性 (T细胞介导) 与冷 (直接瘤/T细胞影响) 瘤中表现出差异性影响.
化合物-182对抗α-PD-1治疗的瘤产生了敏感性,提高了治疗效率.

结论:

针对PTP1B和PTPN2的小分子抑制剂,如Compound-182,具有增强抗瘤免疫力的巨大潜力.
化合物-182代表了各种固体瘤的有希望的治疗候选者,可能改善对检查点抑制剂的反应.
向PTP1B/PTPN2提供了一种可行的策略,通过调节瘤微环境和T细胞功能来对抗癌症.

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