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衰老诱导的血管重塑在胰腺癌中造成治疗脆弱性

Marcus Ruscetti¹, John P Morris¹, Riccardo Mezzadra¹

¹Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

|April 3, 2020

概括

结合MEK和CDK4/ 6抑制剂可诱导KRAS突变胰腺癌的衰老. 这种疗法通过促进瘤血管和免疫细胞透来增强化疗和免疫疗.

科学领域:

癌症学
癌症生物学
免疫疗法

背景情况:

KRAS突变的胰腺管腺癌 (PDAC) 呈现出一种脱膜性肌瘤,导致低血管性,免疫抑制和对标准治疗的抗性.
针对KRAS驱动的信号是克服PDAC治疗耐药性的关键.

研究的目的:

在KRAS突变PDAC中研究结合MEK和CDK4/ 6抑制剂的疗效.
探索治疗诱导衰老及其相关分泌表型 (SASP) 在调节瘤微环境和增强治疗反应中的作用.

主要方法:

使用KRAS突变PDAC的临床前小鼠模型.
使用针对MEK和CDK4/ 6的组合疗法诱导衰老.
分析了治疗诱导的衰老和SASP对瘤血管化,免疫细胞透以及对化疗 (gemcitabine) 和免疫治疗 (PD-1阻断) 的反应的影响.

主要成果:

结合MEK和CDK4/ 6抑制诱导了PDAC细胞中的视网膜母细胞 (RB) 蛋白介导衰老.
治疗诱导的衰老产生了SASP,促进了瘤血管化,改善了gemcitabine的输送和有效性.
通过SASP介导的内皮激活导致CD8+T细胞透的增加,使瘤对PD-1检查点阻塞敏感.

结论:

通过SASP,治疗诱导的衰老可以克服KRAS突变PDAC的低血管性和免疫排除.
这种方法在PDAC模型中确定化学治疗和免疫治疗的新兴易感性.
针对衰老是一种有前途的策略,

关键词:

一个T细胞化学疗法耐药性内皮细胞的激活免疫疗法胰腺癌年老与衰老相关的分泌表型针对性的治疗瘤微环境血管生物学

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