在低氧和多发性骨髓瘤骨髓中,mTOR活性和CD8+ T细胞的代谢重编程受损
Taylor Fulton-Ward1,2, Nancy Gudgeon1,2, Isaac Thirlwell1,2
1Department of Immunology and Immunotherapy, School of Immunity, Infection and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
Blood advances
|September 12, 2025
概括
骨髓缺氧抑制CD8+T细胞抗瘤功能,这对于多发性骨髓瘤 (MM) 治疗至关重要. 这种与代谢变化相关的抑制可能会限制T细胞参与治疗在MM患者中的有效性.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 细胞的新陈代谢
背景情况:
- 新型多发性骨髓瘤 (MM) 疗法向T细胞,但它们在骨髓 (BM) 微环境中的有效性有限.
- 皮质细胞具有特征性缺氧,特别是在MM中,可能会损害T细胞功能.
研究的目的:
- 调查低氧对与MM相关的CD8+T细胞反应的影响.
- 阐明MM中低氧诱导的T细胞功能障碍背后的分子机制.
- 评估缺氧对MM中T细胞诱导疗法的影响.
主要方法:
- 在低氧条件下评估了CD8+T细胞激活,增殖,细胞因子分泌 (IFN-γ,TNF-α) 和细胞毒性.
- 分析了关键的代谢调节剂,包括mTOR,c-Myc,BNIP3和Rheb.
- 在低氧条件下评估了BCMA×CD3双特异抗体的活性,并分析了患者衍生的BM CD8+ T细胞.
主要成果:
- 缺氧严重抑制了CD8+T细胞激活,增殖和IFN-γ分泌,而细胞毒性和TNF-α表达没有受到影响.
- 缺氧降低了mTOR活性,c-Myc表达,糖解和线粒体谷氨酸氧化,与升高的BNIP3和降低Rheb.相关.
- 双特异性抗体的有效性在低氧下受损,MM患者的BM CD8+ T细胞显示出减少的增殖,c-Myc和Rheb,BNIP3升高.
结论:
- 骨髓缺氧会损害关键的CD8+T细胞功能,包括激活和增殖,可能会限制基于T细胞的MM免疫疗法的有效性.
- 观察到的T细胞功能障碍在机理上与细胞代谢改变有关,这是由缺氧诱导的BNIP3和Rheb.的变化所驱动的.
- 研究结果表明,在BM微环境中克服缺氧或增强T细胞功能的策略可能会改善MM治疗结果.
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