Department of Hematology, Cancer Center Amsterdam.
Lymphoma and Myeloma Center Amsterdam, and.
Blood Adv. 2022 Jul 26;6(14):4185-4195. doi: 10.1182/bloodadvances.2022007034.
Acquired T-cell dysfunction is characteristic of chronic lymphocytic leukemia (CLL) and is associated with reduced efficacy of T cell-based therapies. A recently described feature of dysfunctional CLL-derived CD8 T cells is reduced metabolic plasticity. To what extend CD4 T cells are affected and whether CD4 T-cell metabolism and function can be restored upon clinical depletion of CLL cells are currently unknown. We address these unresolved issues by comprehensive phenotypic, metabolic, transcriptomic, and functional analysis of CD4 T cells of untreated patients with CLL and by analysis of the effects of venetoclax plus obinutuzumab on the CD4 population. Resting CD4 T cells derived from patients with CLL expressed lower levels of GLUT-1 and displayed deteriorated oxidative phosphorylation (OXPHOS) and overall reduced mitochondrial fitness. Upon T-cell stimulation, CLL T cells were unable to initiate glycolysis. Transcriptome analysis revealed that depletion of CLL cells in vitro resulted in upregulation of OXPHOS and glycolysis pathways and restored T-cell function in vitro. Analysis of CD4 T cells from patients with CLL before and after venetoclax plus obinutuzumab treatment, which led to effective clearance of CLL in blood and bone marrow, revealed recovery of T-cell activation and restoration of the switch to glycolysis, as well as improved T-cell proliferation. Collectively, these data demonstrate that CLL cells impose metabolic restrictions on CD4 T cells, which leads to reduced CD4 T-cell functionality. This trial was registered in the Netherlands Trial Registry as #NTR6043.
获得性 T 细胞功能障碍是慢性淋巴细胞白血病（CLL）的特征，与 T 细胞为基础的治疗效果降低有关。最近描述的功能失调的 CLL 衍生 CD8 T 细胞的一个特征是代谢可塑性降低。目前尚不清楚 CD4 T 细胞受到多大程度的影响，以及在临床清除 CLL 细胞后，CD4 T 细胞代谢和功能是否可以恢复。我们通过对未经治疗的 CLL 患者的 CD4 T 细胞进行全面的表型、代谢、转录组和功能分析，并分析 venetoclax 加 obinutuzumab 对 CD4 群体的影响，来解决这些未解决的问题。来自 CLL 患者的静止 CD4 T 细胞表达较低水平的 GLUT-1，并表现出恶化的氧化磷酸化（OXPHOS）和整体降低的线粒体适应性。在 T 细胞刺激下，CLL T 细胞无法启动糖酵解。转录组分析显示，体外清除 CLL 细胞导致 OXPHOS 和糖酵解途径的上调，并恢复了体外 T 细胞功能。对 venetoclax 加 obinutuzumab 治疗前后 CLL 患者的 CD4 T 细胞进行分析，该治疗导致 CLL 在血液和骨髓中得到有效清除，结果显示 T 细胞激活恢复，糖酵解的转变得到恢复，以及 T 细胞增殖得到改善。总的来说，这些数据表明 CLL 细胞对 CD4 T 细胞施加代谢限制，导致 CD4 T 细胞功能降低。该试验在荷兰试验注册中心注册为 #NTR6043。
