靶向 GEM 重编程巨噬细胞并克服食管鳞状细胞癌的免疫治疗耐药
Targeting GEM Reprograms Macrophages and Overcomes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma.
作者
作者单位
- Zhongshan Hospital China.
- Zhongshan Hospital Shanghai China.
- Fudan University China.
- Fudan University Shanghai China.
摘要
中文
食管鳞状细胞癌（ESCC）对免疫检查点阻断表现出异质性反应，凸显了定义驱动抗 PD-L1 抑制耐药的肿瘤内在机制的必要性。在这里，我们确定了 GTP 结合蛋白（GEM）在骨骼肌中过表达，作为与 ESCC 抗 PD-L1 治疗反应不良相关的肿瘤细胞内在调节因子。肿瘤细胞中的 GEM 表达驱动肿瘤相关巨噬细胞（TAM）介导的免疫抑制，导致 CD8⁺ T 细胞浸润减少和细胞毒性功能受损。机制上，GEM 诱导 SERPINE1 表达，该蛋白分泌并作用于巨噬细胞 LRP1，驱动替代激活并抑制抗肿瘤免疫。GEM 通过 MKK3-RACK1-p38-MEF2A 级联增强 SERPINE1 表达。GEM 信号通过代谢偶联的反馈机制得以加强。暴露于 GEM 高肿瘤细胞的巨噬细胞促进肿瘤细胞糖酵解和乳酸产生，这驱动 AARS1 依赖性 GEM 乳酰化并加强其与 RACK1 的相互作用以放大下游信号。破坏 SERPINE1-LRP1 轴可恢复 CD8⁺ T 细胞活性并增强体内 PD-L1 阻断的反应。对 GEM 依赖性信号的药理学干扰重塑了肿瘤免疫微环境并改善了对 PD-L1 阻断的反应。总之，这些发现定义了一个 GEM-SERPINE1-LRP1 信号轴，驱动巨噬细胞介导的免疫抑制，并表明靶向该通路可能增强 ESCC 中 PD-L1 阻断的疗效。
English
Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to immune checkpoint blockade, highlighting the need to define tumor-intrinsic mechanisms driving resistance to PD-L1 inhibition. Here, we identified GTP-binding protein overexpressed in skeletal muscle (GEM) as a tumor cell-intrinsic regulator associated with poor response to anti-PD-L1 therapy in ESCC. GEM expression in tumor cells drove tumor-associated macrophage (TAM)-mediated immunosuppression, leading to reduced CD8⁺ T cell infiltration and impaired cytotoxic function. Mechanistically, GEM induced SERPINE1 expression that was secreted and acted on macrophage LRP1 to drive alternative activation and suppress antitumor immunity. GEM enhanced SERPINE1 expression through a MKK3-RACK1-p38-MEF2A cascade. GEM signaling was reinforced by a metabolically coupled feedback mechanism. Macrophages exposed to GEM-high tumor cells promoted tumor cell glycolysis and lactate production, which drove AARS1-dependent lactylation of GEM and strengthened its interaction with RACK1 to amplify downstream signaling. Disruption of the SERPINE1-LRP1 axis restored CD8⁺ T cell activity and enhanced response to PD-L1 blockade in vivo. Pharmacological perturbation of GEM-dependent signaling remodeled the tumor immune microenvironment and improved responses to PD-L1 blockade. Together, these findings define a GEM-SERPINE1-LRP1 signaling axis that drives macrophage-mediated immune suppression and suggest that targeting this pathway may enhance the efficacy of PD-L1 blockade in ESCC.
分类与指标
- 研究类型
- 基础研究
- 病种
- 食管癌
- JCR 分区
- Q1
- 影响因子
- 22.6
- 新锐分区
- 1区