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瘤分泌的AGR2诱导树突细胞功能障碍,并降低了LKB1缺乏癌症的免疫治疗疗效

Yuxin Yao^1,2, Yuejun Luo^3,4, Zhanyu Wang^1,2

¹National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Department of Thoracic Surgery, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, Beijing, China.

Journal for immunotherapy of cancer

|October 24, 2025

概括

缺乏LKB1的瘤会损害树突细胞 (DC) 功能,阻碍抗PD-1免疫疗法. 瘤分泌的AGR2稳定了DC中的ARG1,抑制了T细胞的反应,提供了一个治疗点.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
瘤微环境瘤微环境

背景情况:

缺乏LKB1 (STK11) 的瘤会产生一种免疫抑制的微环境,限制抗PD-1疗法的有效性.
这些瘤中免疫逃避的机制,特别是树突细胞 (DC) 功能障碍,尚不清楚.
传统的DC1 (cDC1) 细胞对抗原呈现和T细胞激活至关重要,但它们在LKB1缺乏瘤中的作用需要表征.

研究的目的:

研究LKB1缺陷瘤中免疫逃避的机制,重点关注DC功能障碍.
确定负责DC损伤和T细胞抑制的关键介质.
探索治疗策略,以增强LKB1缺乏癌症的免疫疗法.

主要方法:

在小鼠中使用CRISPR/Cas9 Stk11-knockout瘤细胞系模拟LKB1缺乏症.
通过流细胞计评估DC透和功能,包括迁移和抗原吸收试验.
利用分泌蛋白质组学,LC-MS/MS,共免疫沉和ChIP-qPCR来识别和验证AGR2-ARG1轴及其上游调节.

主要成果:

缺乏LKB1的瘤显示cDC1透率降低和DC功能受损 (抗原吸收,迁移,T细胞原始化).
通过AMPKα-FOXA1通路上调的瘤分泌前部梯度2 (AGR2) 被确定为DC功能障碍的关键调解者.
在DC中,AGR2稳定了阿尔金酶1 (ARG1) 表达,抑制了CD8+T细胞激活. 恢复DC功能增强了抗PD-1的有效性.

结论:

标志着抗原呈现受损和T细胞原始化的DC功能障碍是LKB1缺乏瘤中关键的免疫逃避机制.
瘤分泌的AGR2稳定了DC中的ARG1,抑制了T细胞的反应,并促进了免疫疗法抵抗力.
针对AMPKα-FOXA1-AGR2-ARG1轴或恢复DC功能是改善LKB1缺乏癌症免疫治疗结果的有希望的策略.

关键词:

树突细胞树突细胞免疫治疗是一种免疫疗法.肺癌肺癌是一种肺癌.瘤微环境 - - 瘤微环境疫苗疫苗疫苗疫苗

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