PO.ET03.04 · 实验与分子治疗
克服化疗耐药：通过减轻内质网应激恢复耐药DLBCL细胞的多柔比星敏感性和自然杀伤细胞免疫
Overcoming chemoresistance: Restoring doxorubicin sensitivity and natural killer cell immunity in resistant DLBCL cells through reduction of endoplasmic reticulum stress
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
弥漫性大B细胞淋巴瘤（DLBCL）的复发通常归因于其对多柔比星（DOX）的耐药，这带来了重大的治疗挑战并导致预后不良。内质网（ER）应激在DOX耐药中起关键作用，通过调控肿瘤细胞的存活和免疫逃逸而受到控制。本研究利用小鼠异种移植构建了DOX耐药的DLBCL细胞系，以研究其潜在机制和潜在治疗策略。我们进行了全面分析，聚焦于应激反应通路、癌基因驱动的免疫调节信号以及自然杀伤（NK）细胞的细胞毒活性。耐药细胞表现出IRE1-XBP1s激活和c-MYC表达升高，这削弱了NK细胞介导的肿瘤杀伤并强化了免疫逃逸。通过内质网应激抑制剂BI09抑制XBP1s，有效瓦解了这一代偿性耐药策略，恢复了NK细胞敏感性，并大幅增加了肿瘤细胞凋亡。值得注意的是，BI09与DOX联合使用在降低的DOX浓度下产生了显著的抗淋巴瘤活性，从而克服了化疗耐药。这些发现表明，BI09通过双重途径发挥作用，同时恢复难治性DLBCL的化疗敏感性并对抗c-MYC介导的免疫逃逸。因此，本研究强调了IRE1-XBP1s-c-MYC轴作为DLBCL细胞化疗耐药和免疫抑制中的关键通路，并确定BI09为一种可行的治疗候选药物，能够破坏化疗耐药并增强侵袭性淋巴瘤中免疫化疗的疗效。
查看英文原文 English abstract
The recurrence of diffuse large B-cell lymphoma (DLBCL) is commonly attributed to its resistance to doxorubicin (DOX), which presents a significant therapeutic challenge and contributes to poor prognosis. Endoplasmic reticulum (ER) stress, pivotal in DOX resistance, is governed by regulating the survival of tumor cells and immune evasion. This study developed DOX-resistant DLBCL cell lines using murine xenografts to investigate the underlying mechanisms and potential therapeutic strategies. Comprehensive analyses were performed, focusing on stress-response pathways, oncogene-driven immunomodulatory signaling, and the cytotoxic activity of natural killer (NK) cells. Resistant cells exhibited elevated IRE1-XBP1s activation and c-MYC expression, which compromised NK cell-mediated tumor killing and reinforced immune evasion. Inhibition of XBP1s through ER stress inhibitor BI09 effectively dismantled this compensatory resistance strategy, reinstated NK cell sensitivity, and substantially increased tumor cell apoptosis. Notably, the combination of BI09 with DOX resulted in substantial anti-lymphoma activity at reduced DOX concentrations, thereby overcoming chemoresistance. These findings indicated that BI09 operated through a dual approach, simultaneously restoring chemosensitivity in refractory DLBCL and counteracting c-MYC-mediated immune evasion. Consequently, this study underscored the IRE1-XBP1s-c-MYC axis as a pivotal pathway in chemoresistance and immune suppression in DLBCL cells, and identified BI09 as a viable therapeutic candidate capable of disrupting chemoresistance and enhancing the efficacy of immunochemotherapy in aggressive lymphoma.
利益披露 Disclosure
Y. Lin, None..
C. A. Hu, None..
C. A. Tang, None..
C. Chuang, None..
C. Chen, None.