肿瘤细胞治疗研究
英文原题：Neutrophil extracellular traps promote liver metastasis by impairing NK cell-dependent tumor surveillance via CCDC25.
我们的研究结果确定了CCDC25是NK细胞上潜在的“先天免疫检查点”，揭示了一种有前景的治疗策略，即重新激活NK细胞功能以抑制肝转移。
肿瘤转移需要原发肿瘤细胞与远处器官中的免疫细胞之间持续相互作用，然而这种相互作用如何塑造转移部位不断演变的免疫景观仍不清楚。在此，我们利用4T1原位乳腺癌模型中的纵向单细胞RNA测序，观察到在肝脏转移进展过程中中性粒细胞进行性浸润、强烈的NETosis以及免疫抑制微环境。通过多个体内模型，我们确定巨噬细胞依赖性的中性粒细胞胞外诱捕网（NET）形成是肝转移的有效驱动因素。在机制上，细胞外NET来源的DNA被自然杀伤（NK）细胞上的跨膜蛋白含卷曲螺旋结构域25（CCDC25）感知，NET-CCDC25相互作用通过CCDC25-ILK-STAT3轴下调包括NKG2D、NKp46、NKp44在内的多种活化受体，从而损害NK细胞监视功能。在临床肝转移样本中，较高的NET表达水平与NK细胞功能障碍相关。总体而言，我们的研究结果确定CCDC25是NK细胞上潜在的“固有免疫检查点”，揭示了一种有前景的治疗策略，即重新激活NK细胞功能以抑制肝转移。
Tumor metastasis requires constant crosstalk between primary tumor cells and immune cells in distant organs, yet how this interaction shapes the evolving immune landscape of metastatic sites remains unclear. Here, using longitudinal single-cell RNA sequencing in a 4T1 orthotopic breast cancer model, we observe a progressive infiltration of neutrophils, robust NETosis and an immunosuppressive niche during metastatic progression in the liver. Through multiple in vivo models, we determine that macrophage-dependent neutrophil extracellular trap (NET) formation serves as a potent driver of liver metastasis. Mechanistically, extracellular NET-derived DNA is sensed by the transmembrane protein coiled-coil domain containing 25 (CCDC25) on natural killer (NK) cells, and the NET-CCDC25 interaction impairs NK cell surveillance by downregulating multiple activating receptors, including NKG2D, NKp46, NKp44, via the CCDC25-ILK-STAT3 axis. In clinical metastatic liver samples, a higher level of NET expression is associated with NK cell dysfunction. Overall, our findings identify CCDC25 as a potential "innate immune checkpoint" on NK cells, revealing a promising therapeutic strategy to reactivate NK cell function to inhibit liver metastasis.
MEMBER ACCOUNT
登录成功会直接打开下一页。
