He Mei-Yao, Liu Meng, Yuan Jiayin, Lv Jin, Li Wei, Yan Qianwen, Tang Yujiao, Wang Luyi, Guo Li, Liu Fang
Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China.
School of Life and Health Technology, Dongguan University of Technology, Dongguan, 523808, People's Republic of China.
Sci Rep. 2025 May 7;15(1):15878. doi: 10.1038/s41598-025-00410-x.
Accumulating research suggests that Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma (EBV+DLBCL) is associated with immune dysfunction and tumor microenvironment (TME) heterogeneity. While the prognostic role of the TME in EBV-DLBCL is established, its impact on EBV+DLBCL survival remains unclear. Here, we integrated 10X Visium spatial transcriptomics (ST) with single-cell RNA sequencing (scRNA-seq) to map TME heterogeneity in EBV+DLBCL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified PD-1/PD-L1 signaling as a hallmark of EBV+DLBCL's immunosuppressive TME. Functional validation using the PD-1/PD-L1 inhibitor BMS202 revealed dose-dependent suppression of proliferation and enhanced apoptosis in EBV+Farage cells, with TLR4 emerging as a downstream effector showing EBV-status-dependent regulation. These findings not only link TME-driven PD-1/PD-L1 activation to EBV+DLBCL's poor prognosis but also provide preclinical evidence for PD-1/PD-L1 blockade as a therapeutic strategy.
越来越多的研究表明，爱泼斯坦-巴尔病毒阳性弥漫性大B细胞淋巴瘤（EBV+DLBCL）与免疫功能障碍和肿瘤微环境（TME）异质性有关。虽然TME在EBV阴性DLBCL中的预后作用已得到证实，但其对EBV+DLBCL生存的影响仍不清楚。在这里，我们将10X Visium空间转录组学（ST）与单细胞RNA测序（scRNA-seq）相结合，以描绘EBV+DLBCL中的TME异质性。基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析确定PD-1/PD-L1信号传导是EBV+DLBCL免疫抑制性TME的一个标志。使用PD-1/PD-L1抑制剂BMS202进行的功能验证显示，EBV+法拉吉细胞的增殖受到剂量依赖性抑制，细胞凋亡增加，TLR4作为下游效应物出现，显示出EBV状态依赖性调节。这些发现不仅将TME驱动的PD-1/PD-L1激活与EBV+DLBCL的不良预后联系起来，还为PD-1/PD-L1阻断作为一种治疗策略提供了临床前证据。
