药理性HIF稳定激活了共刺激受体表达,以增加采用T细胞治疗的抗瘤疗效
Walter Jackson Iii1,2, Yongkang Yang1,3, Shaima Salman1,2
1Armstrong Oxygen Biology Research Center and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Science advances
|August 28, 2024
概括
用二甲基甲基甘氨酸 (DMOG) 对T细胞进行体外治疗,通过促进共刺激受体表达来增强采用细胞转移 (ACT) 疗法,从而改善瘤减少和免疫细胞对抗癌症的活性.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 细胞疗法细胞疗法
背景情况:
- 采用细胞转移 (ACT) 是癌症的有前途的免疫疗法.
- 提高T细胞功能对于提高ACT疗效至关重要.
- 低氧诱导因子 (HIF) 在调节T细胞反应方面发挥作用.
研究的目的:
- 为了研究二甲基糖氨酸 (DMOG) 的作用,一个低氧诱导因子 (HIF) 稳定剂,T细胞共刺激受体表达和功能.
- 评估用DMOG治疗的T细胞与辅助刺激受体激动剂结合用于采用细胞转移治疗的治疗潜力.
- 评估这种综合方法对瘤生长和内免疫细胞透和活动的影响.
主要方法:
- 小鼠的CD8+ T细胞用DMOG进行了ex vivo治疗.
- 评估了HIF与共刺激受体基因 (CD81,GITR,OX40,4-1BB) 的结合.
- 测量了T细胞对黑色素瘤细胞的杀死.
- 在携带瘤的小鼠中,采用使用DMOG治疗的T细胞和/或共刺激性受体激素抗体进行了采用细胞转移.
- 分析了内免疫细胞标记物和细胞分解活性.
主要成果:
- DMOG治疗增加了T细胞上辅助刺激受体CD81,GITR,OX40和4-1BB的HIF结合和表达.
- 用DMOG增强的T细胞表现出增加杀死黑色素瘤细胞,进一步增强了激进抗体.
- 使用DMOG治疗的T细胞和激素抗体的ACT显著降低了小鼠的瘤生长.
- 这种疗法增加了内CD8+T细胞,自然杀手细胞和细胞分解标志物.
结论:
- 活体DMOG治疗稳定了HIF,上调T细胞上的共刺激受体.
- 将DMOG增强的ACT与辅助刺激受体激动剂结合起来,是增强抗瘤免疫力的有效策略.
- 这种方法有望改善癌症免疫治疗结果.
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