Chemotherapy-induced cellular senescence promotes stemness of aggressive B-cell non-Hodgkin’s lymphoma via CCR7/ARHGAP18/IKBα signaling activation

作者：Jiyu Wang, Qianshan Tao, Keke Huang, Yangyang Wang, Linhui Hu, Anwen Ren, Huiping Wang, Wan Yang, J. Li, Liuying Yi, Yanjie Ruan, Zhixiang Wanyan, Fan Wu, Zhimin Zhai, Chaohong Liu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-009356 · 被引用次数：8 · 研究领域：Telomeres, Telomerase, and Senescence、Acute Myeloid Leukemia Research、Lymphoma Diagnosis and Treatment

BACKGROUND: Resistance to existing therapies is a major cause of treatment failure in patients with refractory and relapsed B-cell non-Hodgkin's lymphoma (r/r B-NHL). Therapy-induced senescence (TIS) is one of the most important mechanisms of drug resistance. METHODS: This study used single-cell RNA sequencing to analyze doxorubicin-induced senescent B-NHL cells. C-C chemokine receptor 7 (CCR7) expression in patients with aggressive B-NHL was assessed using immunohistochemistry and flow cytometry. Lentiviral transfection was used to target CCR7 expression in Raji and SU-DHL-2 cells. Protein localization was visualized through immunofluorescence, while western blotting and co-immunoprecipitation were used to analyze protein expression and interactions. Cell proliferation was measured with the Cell Counting Kit-8 assay, and senescent cells were detected using senescence-associated β-galactosidase staining. The stemness of cells was evaluated through colony and sphere formation assays. Transwell assays assessed cell migration and invasion. Finally, inhibitors GS143 and Y27632 were used to examine the effect of IKBα and ARHGAP/RhoA inhibition on B-NHL-TIS. RESULTS: Here we identified a distinct group of TIS, composed of memory B-cell population characterized by strong positive expression of CCR7, which was significantly elevated in TIS population compared with normal proliferating and autonomously senescent lymphoma cell populations. Additionally, CCR7 expression was significantl...