Liu Chunlan, Ding Tianjian, Zou Rong, Zhang Aili, Zhi Zhengzhuo, Wang Sili
Department of Hematology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China.
BMC Cancer. 2025 Apr 21;25(1):745. doi: 10.1186/s12885-025-14166-0.
As part of the innate immune system, NK cells contribute to optimizing cancer immunotherapy strategies and are becoming a focal point in cancer research. However, limited research has been conducted to further investigate changes in NK cell subsets and their critical genes following ibrutinib treatment in CLL patients.
Peripheral blood samples from patients clinically and pathologically diagnosed with monoclonal B-cell lymphocytosis (MBL), newly diagnosed with CLL (ND-CLL), postibrutinib-treated patients who achieved a complete response (CR) or partial response (PR), and those with Richter's syndrome (RS) were collected. Single-cell transcriptome sequencing was performed, followed by pseudotemporal analysis and functional enrichment to characterize the NK cell subsets. Mendelian randomization analysis and colocalization analysis were employed to identify key genes. Multiple algorithms were used for immune infiltration analysis, and drug sensitivity analysis was conducted to pinpoint potential therapeutic agents.
Three distinct NK cell subsets were identified: CD56bright_NK cells, CD56dim_NK cells, and a highly cytotoxic CLL_NK subset. The core genes of the CLL_NK subset were elucidated through Mendelian randomization and colocalization analyses. A cell subset-specific novel index (CNI) was constructed based on these core genes and was shown to be capable of predicting responses to immunotherapy. Oncopredictive algorithms and molecular docking screenings further identified semaxanib and ulixertinib as potential therapeutic candidates for CLL.
The CLL_NK subset plays a crucial role in the development and progression of CLL. The CNI, derived from its key genes, holds promise as a predictor of immune therapeutic responses, highlighting the significance of CLL_NK subset dynamics and their genetic underpinnings in CLL management.
作为固有免疫系统的一部分，自然杀伤（NK）细胞有助于优化癌症免疫治疗策略，正成为癌症研究的焦点。然而，关于依鲁替尼治疗慢性淋巴细胞白血病（CLL）患者后NK细胞亚群及其关键基因变化的进一步研究较少。
收集临床和病理诊断为单克隆B细胞淋巴细胞增多症（MBL）、新诊断为CLL（ND-CLL）、依鲁替尼治疗后达到完全缓解（CR）或部分缓解（PR）的患者以及患有 Richter 综合征（RS）患者的外周血样本。进行单细胞转录组测序，随后进行伪时间分析和功能富集以表征NK细胞亚群。采用孟德尔随机化分析和共定位分析来鉴定关键基因。使用多种算法进行免疫浸润分析，并进行药物敏感性分析以确定潜在的治疗药物。
鉴定出三个不同的NK细胞亚群：CD56bright_NK细胞、CD56dim_NK细胞和高细胞毒性的CLL_NK亚群。通过孟德尔随机化和共定位分析阐明了CLL_NK亚群的核心基因。基于这些核心基因构建了细胞亚群特异性新指标（CNI），并显示其能够预测免疫治疗反应。肿瘤预测算法和分子对接筛选进一步确定司马沙尼和乌利昔替尼为CLL的潜在治疗候选药物。
CLL_NK亚群在CLL的发生和发展中起关键作用。源自其关键基因的CNI有望作为免疫治疗反应的预测指标凸显了CLL_NK亚群动态及其遗传基础在CLL管理中的重要性。
