卡尔-T细胞和T细胞的表型和功能受到不同程度的葡萄糖皮质体暴露的影响
Thomas Poiret1, Sara Vikberg2, Esther Schoutrop2
1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. thomas.poiret@ki.se.
Journal of translational medicine
|March 13, 2024
概括
葡萄糖皮质类药物 (GCs) 损害了仿制抗原受体 (CAR) T细胞功能和抗瘤活性,其影响因CAR类型而异. 在GC退出后,恢复是可能的,强调需要了解这些相互作用.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞疗法细胞疗法
- 药理学 药理学是指药理学的学科.
背景情况:
- 化学抗原受体 (CAR) T细胞疗法具有强大的抗癌活性,但具有诸如细胞因子释放综合征 (CRS) 和免疫效应细胞相关神经毒性综合征 (ICANS) 等不良事件的风险.
- 葡萄糖皮质类药物 (GCs) 是高级CRS和ICANS的标准治疗方法,但它们对CAR T细胞疗效的潜在负面影响需要进一步研究.
- 了解GC和CAR-T细胞之间的相互作用对于优化治疗策略和患者的治疗结果至关重要.
研究的目的:
- 为了比较甲 (Dx) 和甲基前醇 (MP) 对不同类型的CAR T细胞的表型和功能影响.
- 评估GC暴露对CAR T细胞抗瘤活性的影响,并确定影响治疗反应的因素.
- 评估CAR T细胞中GC诱导的变化的可逆性.
主要方法:
- 使用了CD19,美索-CD28 (M28z) 和美索-41BB (MBBz) 的CAR T细胞进行比较分析.
- 暴露于甲基 (Dx) 或甲基 (MP) 的CAR T细胞和评估的表型变化,包括受体表达 (GC受体,PD-1,TIM-3,LAG-3) 和T细胞耗尽标志物.
- 测量功能能力 (例如CD107a,INFγ,TNF,IL-2) 和抗瘤活性,比较CAR T细胞类型之间的反应以及CD4+和CD8+T细胞子集之间的反应.
主要成果:
- 葡萄糖皮质体受体水平在差异较小的CAR T细胞中较高.
- GC暴露增加了PD-1和TIM-3的表达,同时降低了LAG-3和T细胞的整体功能,无论是在未转化和CAR T细胞中.
- 与CD19 CAR T细胞相比,GCs在未转化的T细胞中引起了更大的疲劳和功能障碍,并且对CD4+比CD8+和CD19 CAR T细胞产生了更大的影响.
- 与GC暴露后的MBBz CAR T细胞相比,M28z CAR T细胞显示PD-1表达增加和增殖/功能减少.
- 重复暴露于GC后,CAR T细胞的抗瘤活性显著受损,但在GC停用后48小时内出现部分恢复.
结论:
- 葡萄糖皮质类药物对未转化和CAR T细胞的表型和功能产生差异性影响.
- CAR的特定辅助刺激领域影响了CAR T细胞对GCs反应的程度.
- 这些发现强调了在CAR T细胞治疗的背景下考虑GC治疗的重要性,以减轻对疗效的潜在负面影响.
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