Jacobs Chaja F, Peters Fleur S, Camerini Elena, Cretenet Gaspard, Rietveld Joanne, Schomakers Bauke V, van Weeghel Michel, Hahn Nico, Verberk Sanne G S, Van den Bossche Jan, Langeveld Mirjam, Kleijwegt Fleur, Eldering Eric, Zelcer Noam, Kater Arnon P, Simon-Molas Helga
Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Department of Hematology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
Cell Mol Immunol. 2025 May;22(5):485-500. doi: 10.1038/s41423-025-01262-1. Epub 2025 Mar 4.
Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.
自体T细胞疗法在慢性淋巴细胞白血病（CLL）中疗效有限，因为该病存在获得性免疫功能障碍。在CLL中，线粒体代谢紊乱与T细胞活化和增殖缺陷有关。最近的研究表明，脂质代谢调节T细胞中的线粒体功能和分化，但其在CLL中的作用仍未得到探索。这项全面的研究比较了CLL患者和健康供体的T细胞脂质代谢，揭示了TCR介导的活化后人类T细胞扩增对外源胆固醇的关键依赖性。通过多组学和功能分析，我们发现CLL患者（CLL T细胞）的活性冷冻样本中的T细胞对胆固醇剥夺的适应性受损，关键脂质代谢转录因子的上调不足。CLL T细胞表现出脂质储存改变，三酰甘油增加而胆固醇减少，脂肪酸氧化（FAO）效率低下。使用先天性FAO障碍患者的样本研究了T细胞中FAO降低的功能后果。FAO降低与较低的T细胞活化相关，但不影响增殖。这表明低胆固醇水平是限制CLL中T细胞增殖的主要因素。CLL T细胞显示脂质筏较少且聚集程度较低，这可能解释了在这些患者中观察到的免疫突触形成受损。我们的研究结果突出了脂质代谢的显著破坏是CLL T细胞功能缺陷的驱动因素，强调了胆固醇在T细胞增殖中的关键作用。这项研究表明，调节胆固醇代谢可以增强CLL中的T细胞功能，为改善这种具有挑战性的疾病的预后提供了新的免疫治疗方法。
