在慢性淋巴细胞白血病中,T细胞功能障碍由伪阴极症和自身隐性纯能信号传递引起的
Chiara Montironi1,2,3, Chaja F Jacobs1,2,3,4, Gaspard Cretenet1,2,3,4
1Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Blood advances
|August 8, 2023
概括
慢性淋巴细胞白血病 (CLL) 细胞诱导T细胞功能障碍,通过创建一个伪催眠状态,损害T细胞代谢和功能. 通过减少白血病负担和调节缺氧和纯能通路来恢复T细胞功能是可能的.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 代谢研究研究 代谢研究
背景情况:
- 获得的T细胞功能障碍是慢性B细胞恶性瘤的常见并发症.
- T细胞代谢与T细胞功能密切相关.
- 恶性细胞可以通过代谢变化诱导T细胞功能障碍.
研究的目的:
- 为了研究由恶性细胞诱导的T细胞功能障碍背后的代谢变化.
- 探索伪阴极症和腺在慢性淋巴细胞白血病 (CLL) 中T细胞功能障碍中的作用.
- 评估调节低氧和纯能通路的治疗潜力,以恢复T细胞功能.
主要方法:
- 使用B细胞恶性细胞系和人体外围血液单核细胞建立了癌症诱导的T细胞功能障碍模型.
- 分析了T细胞代谢组的变化,包括诱导伪催状态和氧化酸化受损 (OXPHOS).
- 研究了免疫抑制性腺素的作用及其对T细胞激活的影响,并评估了联合治疗 (venetoclax和obinutuzumab) 对初级CLL样本中T细胞功能的影响.
主要成果:
- 来自CLL的B细胞系,但不是其他B细胞恶性瘤,在T细胞中诱导了伪低氧状态,使其保持在有氧糖解中,并阻止切换到OXPHOS.
- T细胞产生免疫抑制性腺,抑制T细胞激活,通过阻断腺受体可逆.
- 在初级CLL样本的T细胞中观察到类似的缺氧样特征,该特征在CLL细胞枯竭后是可逆的ex vivo和 in vivo减少白血病负担后的组合疗法,恢复T细胞功能.
结论:
- 一个伪缺氧程序与CLL中的T细胞功能障碍有关.
- 调节缺氧和纯能途径具有恢复CLLT细胞功能的治疗潜力.
- 针对T细胞的代谢变化可能是一个有前途的策略,以克服癌症诱导的T细胞功能障碍.
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