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依赖MCT4的乳酸分泌抑制了LKB1缺乏肺腺癌的抗瘤免疫力

Yu Qian¹, Ana Galan-Cobo¹, Irene Guijarro¹

¹Department of Thoracic/Head and Neck Medical Oncology, Houston, TX, USA.

|June 16, 2023

概括

肺癌中STK11/LKB1的丢失会增加乳酸,抑制抗瘤免疫力,并导致对免疫疗法的抵抗力. 向乳酸生产或其受体可能会逆转这种抵抗.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
分子生物学分子生物学

背景情况:

失活STK11/LKB1突变是KRAS突变肺腺癌 (LUAD) 免疫治疗初级耐药性的关键驱动因素.
这种阻力背后的精确机制尚未完全理解.

研究的目的:

阐明STK11/LKB1突变在LUAD中对免疫治疗产生抗性的机制.
调查乳酸及其相关途径在LUAD中介导免疫抑制中的作用.
探索针对乳酸代谢的治疗策略,以克服免疫治疗耐药性.

主要方法:

在LKB1损失的小鼠模型中单细胞RNA分析.
通过MCT4载体产生的乳酸和分泌物的分析.
评估免疫细胞两极分化 (M2巨细胞) 和T细胞功能.
在体内研究中,使用合成的小鼠模型进行MCT4淘汰或GPR81阻断.
从STK11/LKB1突变LUAD患者的瘤样本的分析.

主要成果:

失去LKB1会增强乳酸的产生和分泌,这种分泌由MCT4转运体介导.
缺乏LKB1的瘤呈现出增加的M2巨细胞极化和功能低下的T细胞.
外源乳酸重现了这些免疫抑制作用,而MCT4敲击或GPR81阻断则取消了它们.
MCT4淘汰赛逆转了由LKB1损失引起的PD-1阻塞阻力.
人类STK11/LKB1突变LUAD瘤表现出类似的免疫表型.

结论:

乳酸盐通过促进M2巨分化和T细胞功能障碍来抑制抗瘤免疫力.
向乳酸通路 (MCT4,GPR81) 是一个有希望的策略,可以逆转STK11/LKB1突变LUAD的免疫疗法耐药性.
这项研究提供了LKB1状态,乳酸代谢和肺癌中的免疫逃避之间的机制联系.

关键词:

一个LKB1一个LKB1 在MCT4中,MCT4是MCT4.在PD-1中使用PD-1.在T细胞激活过程中,免疫疗法耐药性免疫疗法耐药性乳酸乳酸是一种乳酸.肺部腺癌的癌症.巨细胞的两极分化代谢代谢代谢代谢

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