食管癌形成过程中 Krüppel-like factor 4 (KLF4) 表达下调促进免疫逃逸并削弱免疫治疗疗效
Krüppel-like factor 4 downregulation during esophageal cancer formation facilitates immune evasion and impairs immunotherapy.
作者
作者单位
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China.
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China. lindx@cicams.ac.cn.
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China. chenwu@cicams.ac.cn.
摘要
中文
抗原加工和提呈障碍是肿瘤免疫逃逸的关键环节,但其潜在机制尚未完全阐明。本研究揭示,在肿瘤发生过程中 Krüppel-like factor 4 (KLF4) 表达下调在这一免疫决定性过程中发挥重要作用。我们发现,KLF4 表达受抑会导致食管癌中 MHC class I 产量减少,形成免疫抑制微环境,从而限制 CD8⁺ T 细胞浸润。在机制上,KLF4 缺失降低了 MHC class I 位点的染色质可及性及 enhanceosome 复合物的形成,从而抑制 MHC class I 表达。在小鼠同种移植模型中,KLF4 缺失促进肿瘤进展并导致免疫治疗耐药。超出食管癌范畴,我们进一步揭示在多种人类肿瘤中,KLF4 低表达与免疫治疗高失败率显著相关。我们证实,药理学诱导 KLF4 可增强抗原提呈、提高 CD8⁺ T 细胞活性,并在小鼠模型中改善对 PD-1 阻断的治疗效果。这些发现拓展了肿瘤免疫学的知识体系,并为改进肿瘤免疫治疗提供了新视角。
English
Impaired antigen processing and presentation are critical for cancer immune evasion, but the underlying mechanism is not fully known. Here, we show that downregulation of Krüppel-like factor 4 (KLF4) expression during the development of cancer is essential in this immuno-decisive process. We find that suppressed KLF4 expression causes diminished MHC class I production in esophageal cancer, forming immunosuppressive niches that limit CD8⁺ T cell infiltration. Mechanistically, KLF4 loss reduces chromatin accessibility at the MHC class I loci and the enhanceosome complex formation, suppressing MHC class I expression. In mouse allografts, KLF4 loss promotes tumor progression and immunotherapy resistance. Extending beyond esophageal cancer, we reveal that low KLF4 levels are significantly correlated with high immunotherapy failure rates across multiple human cancer types. We demonstrate that pharmacological induction of KLF4 results in enhanced antigen presentation, increases activity of CD8⁺ T cells and improves therapeutic efficacy to PD-1 blockade in mouse models. These findings extend our knowledge of cancer immunology and provide a novel insight for improving cancer immunotherapy.
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
- 81.2
- 新锐分区
- 1区