Despite its immunogenic nature, bladder cancer (BCa) responds sub-optimally to FDA-approved immunotherapy. Background/Objectives: We have previously shown that natural killer (NK) cells are major contributors to overall patient survival in BCa. In our efforts to identify clinically approved agents that enhance NK cell activation, we identified eribulin, a microtubule destabilizer primarily used in breast cancer. Ongoing clinical trials are investigating the potential integration of eribulin into the standard of care in BCa; however, the mechanistic rationale for these trials remains unclear. Methods: Here, we explore the effects of low-dose eribulin on direct NK cell activation in vitro, including on primary patient samples, and in vivo utilizing multiple murine models. Flow cytometry and RNA sequencing were employed to identify the mechanism of NK cell activation by eribulin, which was associated with increased migration and cytotoxicity of NK cells against BCa cells. Results: We found that localized eribulin instillation significantly reduces bladder tumor burden and improves survival in primary BCa in an NK cell-dependent manner. Importantly, eribulin promoted the shift of patient-derived intratumoral NK cells towards an anti-tumor CD49a+CD103+NK subset (ieILC1-like) while diminishing the dysfunctional NR4A2-expressing CD49a−NK subset. Moreover, it decreased the overall expression of exhaustion markers on NK cells, a pattern replicated in our murine models. Conclusions: These findings are paradigm-shifting given that chemotherapy is traditionally considered immunosuppressive. Our study reveals the novel effect of low-dose eribulin chemotherapy in inhibiting bladder tumor growth by enhancing anti-tumor NK cell immunity, challenging previous assumptions and opening new therapeutic approaches to improve antitumor immunity.
尽管膀胱癌具有免疫原性，其对美国食品药品监督管理局批准的免疫疗法反应欠佳。研究背景与目的：我们既往研究表明自然杀伤细胞是影响膀胱癌患者总体生存的关键因素。在筛选可增强自然杀伤细胞活性的临床获批药物过程中，我们发现主要用于乳腺癌治疗的微管去稳定剂艾日布林具有该潜力。当前临床试验正在探索将艾日布林纳入膀胱癌标准治疗方案的可行性，但这些试验的机制依据尚不明确。研究方法：本研究通过体外实验（包括原代患者样本）及多种小鼠体内模型，探讨低剂量艾日布林对自然杀伤细胞直接活化的影响。采用流式细胞术和RNA测序技术解析艾日布林激活自然杀伤细胞的机制，发现其与增强自然杀伤细胞迁移能力及对膀胱癌细胞的杀伤作用相关。研究结果：局部灌注艾日布林能显著降低膀胱肿瘤负荷，并以自然杀伤细胞依赖的方式改善原发性膀胱癌生存期。值得注意的是，艾日布林促使患者来源的肿瘤内自然杀伤细胞向抗肿瘤CD49a+CD103+NK亚群（即ILC1样细胞）转化，同时减少功能异常的NR4A2表达型CD49a−NK亚群。此外，该药物能降低自然杀伤细胞耗竭标志物的整体表达水平，这一现象在小鼠模型中得以复现。研究结论：传统观点认为化疗具有免疫抑制作用，而本研究结果颠覆了这一认知。我们首次揭示低剂量艾日布林化疗通过增强抗肿瘤自然杀伤细胞免疫来抑制膀胱肿瘤生长，这既挑战了既往认知，也为改善抗肿瘤免疫治疗开辟了新途径。
Low-Dose Eribulin Promotes NK Cell-Mediated Therapeutic Efficacy in Bladder Cancer
肿瘤(癌症)患者之家