天生的免疫重塑通过巨细胞-NK细胞交叉声调驱动治疗抵抗
bioRxiv : the preprint server for biology
|August 8, 2025
概括
瘤微环境 免疫细胞在向治疗期间发生变化. 巨细胞在回归过程中招募NK细胞,但这在残留疾病中停止,导致耐药性. 针对这种巨细胞-NK细胞相互作用可以改善癌症治疗.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 癌症生物学 癌症生物学
背景情况:
- 瘤微环境 (TME) 在癌症治疗期间动态变化,影响治疗结果.
- 了解治疗期间TME内的时间免疫变化对于开发有效的组合策略至关重要.
研究的目的:
- 在小鼠黑色素瘤模型中调查针对性治疗期间的免疫动态.
- 确定驱动治疗耐药性的关键细胞相互作用,并探索治疗点.
主要方法:
- 在小鼠黑色素瘤模型和人类癌症患者样本上利用单细胞RNA测序 (scRNA-seq).
- 使用的巨细胞耗尽模型 (LysM-cre;iDTR) 和药理上抑制Ptpn22.
- 对免疫细胞透和信号通路进行了纵向分析.
主要成果:
- 在向治疗期间确定了从炎症转变为免疫排除的TME的转变,与耐药残留疾病有关.
- 发现了一种特定的巨细胞子集,通过瘤回归过程中通过CCR2/5信号调节NK细胞的招募.
- 证明在残留疾病中抑制Ptpn22可以恢复NK细胞的招募,并提高治疗疗效.
- 在人类黑色素瘤和肺癌患者的向治疗期间观察到动态NK细胞透,与治疗结果相关.
结论:
- 在TME内的免疫进化驱动了针对性治疗的获得性耐药性.
- 巨细胞-NK细胞交叉是克服免疫排斥的关键,治疗性可行的轴.
- 针对这一轴有望改善针对性治疗在各种癌症类型中的疗效.
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