IL-18在代谢上重编程CAR表达的自然杀手T细胞,并增强它们的抗瘤活性
Gabriel A Barragán Bravo1, David A de la Cerda1, Elisa Landoni2
1Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center; Department of Pediatrics, Baylor College of Medicine; Houston, Texas, 77030, USA.
概括
介质素-18 (IL-18) 增强了化学抗原受体 (CAR) - 不变的自然杀手T细胞 (NKT) 治疗癌症的作用. IL-18增强了CAR-NKT功能并控制了瘤,提供了一种有前途的下一代免疫治疗方法.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症治疗 癌症治疗
- 细胞工程 细胞工程
背景情况:
- 不变的自然杀手T细胞 (NKT) 具有固有的抗瘤能力,这使得它们对仿真抗原受体 (CAR) 免疫疗法具有吸引力.
- 通过转基因细胞因子表达来增强细胞疗法,可以显著提高它们对各种癌症的效力.
研究的目的:
- 调查单独或与INTERLEUKIN-15 (IL-15) 联合表达的INTERLEUKIN-18 (IL-18) 是否可以增加CAR-NKT细胞的治疗潜力.
- 评估IL-18和IL-15联合表达对CAR-NKT细胞功能,瘤控制和潜在毒性的影响.
主要方法:
- 在人类NKT中生成逆转录病毒结构,用于与可诱导的caspase 9安全开关共同表达IL-15和/或IL-18.
- NKT 与 GD2 特定的 CAR 的协同转化以及体外细胞毒性,增殖和细胞因子分泌的评估.
- 在转移性神经母细胞瘤模型中的体内评估和涉及转录概况和向代谢学的机制研究.
主要成果:
- 与单独IL-15相比,IL-18或IL-15/IL-18的联合表达显著增强了CAR-NKT细胞毒性,增殖和细胞因子分泌.
- IL-18改善了对肝细胞癌和B细胞白血病模型的CAR-NKT活性.
- 虽然IL-18表达的CAR-NKT在神经母细胞瘤中表现出优异的瘤控制,但IL-15/IL-18组表现出严重的毒性;IL-18诱导了明显的代谢重编程,包括增强的氧化酸化和糖解.
结论:
- IL-18显示出增强基于CAR-NKT细胞的癌症免疫疗法的显著潜力.
- IL-18在CAR-NKTs中驱动独特的代谢和转录程序,与IL-15不同,导致改善抗瘤功能.
- IL-18代表了一种有前途的细胞因子,用于开发下一代,强效和潜在的更安全的CAR-NKT癌症疗法.
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