在固体瘤中克服免疫检查点阻塞抵抗,通过间歇性ITK抑制
Manzhi Zhao1,2, Ling Li1, Caoimhe H Kiernan1
1Department of Immunology, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Scientific reports
|September 21, 2023
概括
间歇性ITK抑制剂治疗重新激活了耗尽的细胞毒性CD8+T细胞 (CTL),增强了免疫检查点阻塞 (ICB) 疗法. 这种方法对ICB耐药的固体瘤如黑色素瘤,中皮质瘤和胰腺癌具有前途.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 药理学 药理学 是一个学科.
背景情况:
- 由慢性抗原刺激驱动的细胞毒性CD8+T细胞 (CTL) 耗尽,限制了癌症免疫治疗的有效性.
- 免疫检查点封锁 (ICB) 已显示出临床益处,但在许多固体瘤中面临阻力.
- T细胞受体 (TCR) 信号传递在T细胞激活和衰竭中起着至关重要的作用.
研究的目的:
- 调查通过IL2诱导的T细胞激酶 (ITK) 抑制剂调节慢性抗原刺激和TCR信号是否可以克服固体瘤中的ICB抵抗.
- 为了确定间歇性ITK抑制与ICB治疗相结合的疗效.
- 阐明ITK抑制对耗尽的CTLs的直接影响.
主要方法:
- 在体内间歇性治疗ICB抗性固体瘤 (黑色素瘤,中皮质瘤,胰腺癌) 用ITK抑制剂.
- 在体外评估ITK抑制耗尽的CTL功能,包括细胞因子的产生,抑制性受体表达和TOX转录因子水平.
主要成果:
- 间歇性ITK抑制在三个不同的ICB耐药固体瘤模型中显著改善了ICB治疗.
- 在试验室中,ITK抑制直接恢复了耗尽的CTLs.
- 增强了CTL功能的关键指标,包括增加了细胞因子的产生和降低了抑制性受体表达和TOX水平.
结论:
- 间歇性ITK抑制是一种可行的策略,可以直接改善CTL耗尽.
- 这种方法可以提高免疫疗法的有效性,包括ICB,即使在通常具有抗药性的固体瘤中.
- 准ITK为改善挑战性瘤类型的癌症治疗结果提供了潜在的治疗途径.
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