Hassouneh Zaineb, Noel Onika D V, Ji Niannian, Kim Michelle E, Svatek Jordan, Svatek Robert S, Risinger April L, Mukherjee Neelam
Department of Microbiology, Immunology & Molecular Genetics, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA.
Department of Urology, University of Texas Health San Antonio (UTHSA), San Antonio, TX 78229, USA.
Cancers (Basel). 2024 Nov 19;16(22):3875. doi: 10.3390/cancers16223875.
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.
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.
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.
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（BCa）具有免疫原性，但对美国食品药品监督管理局（FDA）批准的免疫疗法反应欠佳。
背景/目的：我们之前已经表明，自然杀伤（NK）细胞是BCa患者总体生存的主要贡献者。在我们努力确定可增强NK细胞活化的临床批准药物时，我们发现了艾日布林，一种主要用于乳腺癌的微管稳定剂。正在进行的临床试验正在研究将艾日布林纳入BCa标准治疗方案的可能性；然而，这些试验的机制原理仍不清楚。
在这里，我们探讨低剂量艾日布林对体外直接NK细胞活化的影响，包括对原发性患者样本的影响，并在体内利用多种小鼠模型进行研究。采用流式细胞术和RNA测序来确定艾日布林激活NK细胞的机制，这与NK细胞对BCa细胞的迁移增加和细胞毒性增加有关。
我们发现局部滴注艾日布林以NK细胞依赖的方式显著降低膀胱肿瘤负担并改善原发性BCa患者的生存。重要的是，艾日布林促使患者来源的肿瘤内NK细胞向抗肿瘤的CD49a CD103 NK亚群（即ILC1样）转变，同时减少表达功能失调的NR4A2的CD49a NK亚群。此外，它降低了NK细胞上耗竭标志物的总体表达，这种模式在我们的小鼠模型中也有重现。
鉴于传统上认为化疗具有免疫抑制作用，这些发现具有范式转变的意义。我们的研究揭示了低剂量艾日布林化疗通过增强抗肿瘤NK细胞免疫来抑制膀胱肿瘤生长的新作用，挑战了先前的假设，并开辟了改善抗肿瘤免疫的新治疗方法。
