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DLL1-响应的PD-L1瘤相关巨细胞在乳腺癌中促进内分泌抵抗

Shailesh Singh^1,2, Claudia Weindorfer^1,2,3, Ajeya Nandi⁴

¹Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

Science translational medicine

|November 5, 2025

概括

研究人员确定了免疫抑制性巨细胞,这些巨细胞在雌激素受体阳性乳腺癌中驱动内分泌抵抗. 结合针对这些巨细胞和瘤的疗法,为患者提供了一个有前途的新治疗策略.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
内分泌学在内分泌学.

背景情况:

雌激素受体阳性 (ER+) 乳腺癌是常见的,但内分泌耐药性给治疗带来了挑战.
瘤微环境 (TME) 和免疫治疗在内分泌抵抗性ER+乳腺癌中的作用尚不清楚.
缺乏免疫能力模型阻碍了对免疫细胞参与内分泌抵抗的研究.

研究的目的:

研究瘤相关巨细胞 (TAMs) 在ER+乳腺癌内分泌治疗耐药性的作用.
确定TAMs促进对他莫西芬 (TMX) 和富尔韦斯坦 (FV) 耐药性的机制.
评估针对TAM和瘤细胞的组合疗法的疗效.

主要方法:

开发了ER+乳腺癌的新免疫能力小鼠模型.
鉴定了一种免疫抑制,编程死亡干1-阳性 (PD-L1+) TAMs的亚型.
研究了TAMs通过Delta样联体1 (DLL1) / Notch信号传递和CCR3 / CCL7轴的招募.
在小鼠模型和患者衍生实验物中测试了用抗DLL1,抗PD-L1抗体和TMX的组合疗法.

主要成果:

鉴定了类似M2的PD-L1+TAMs,通过维持癌症干细胞 (CSC) 活动来促进对TMX和FV的抵抗力.
证明瘤细胞表达的DLL1通过CCR3/CCL7轴招募这些TAM.
表明组合疗法 (抗DLL1,抗PD-L1,TMX) 减少了瘤生长和中枢神经瘤.
在组合治疗后观察到免疫抑制TME的重编程.

结论:

特定的TAMs对ER+乳腺癌中的内分泌抵抗有着关键的作用.
针对DLL1和PD-L1与内分泌疗法结合,可以克服耐药性.
这项临床前研究为ER+乳腺癌患者的新型免疫内分泌联合治疗提供了基础.

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