Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen, 518055, China.
Shenzhen University Clinical Medical Academy, Shenzhen, 518055, China.
Apoptosis. 2024 Apr;29(3-4):331-343. doi: 10.1007/s10495-023-01893-7. Epub 2023 Oct 17.
Tumor immune escape is an important manner for colon cancer to escape effective killing by immune system. Currently, the immune checkpoint PD-1/PD-L1-targeted immunotherapy has emerged as a promising therapeutic strategy in colon cancer. Here, present work aims to investigate the biological function of N-methyladenosine (mA) reader insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) in regulating colon cancer's immune escape and CD8 + T cells-mediated tumor cytotoxicity and apoptosis. Results illustrated that IGF2BP1 was closely correlated to the colon cancer patients' poor clinical outcome. Functionally, upregulation of IGF2BP1 suppressed the CD8 T-cells mediated antitumor immunity through reducing their tumor cytotoxicity. Mechanistically, MeRIP-Seq revealed that programmed death ligand 1 (PD-L1) mRNA had a remarkable mA modified site on 3'-UTR genomic. Moreover, PD-L1 acted as the target of IGF2BP1, which enhanced the stability of PD-L1 mRNA. Overall, these results indicated that IGF2BP1 targeted PD-L1 to accelerate the immune escape in colon cancer by reducing CD8 + T cells-mediated tumor cytotoxicity in mA-dependent manner. The findings demonstrate the potential of mA-targeted immune checkpoint blockade in colon cancer, providing a novel insight for colon cancer immune escape and antitumor immunity in further precise treatment.
肿瘤免疫逃逸是结肠癌逃避免疫系统有效杀伤的重要方式。目前，免疫检查点 PD-1/PD-L1 靶向免疫疗法已成为结肠癌有前途的治疗策略。在这里，本研究旨在探讨 N6-甲基腺苷（m6A）阅读器胰岛素样生长因子 2 mRNA 结合蛋白 1（IGF2BP1）在调节结肠癌免疫逃逸和 CD8+T 细胞介导的肿瘤细胞毒性和细胞凋亡中的生物学功能。结果表明，IGF2BP1 与结肠癌患者的不良临床结局密切相关。功能上，IGF2BP1 的上调通过降低 CD8 T 细胞的肿瘤细胞毒性来抑制 CD8 T 细胞介导的抗肿瘤免疫。机制上，MeRIP-Seq 揭示 PD-L1 mRNA 在 3'-UTR 基因组上有一个显著的 mA 修饰位点。此外，PD-L1 是 IGF2BP1 的靶标，增强了 PD-L1 mRNA 的稳定性。总的来说，这些结果表明 IGF2BP1 通过依赖 mA 的方式靶向 PD-L1 减少 CD8+T 细胞介导的肿瘤细胞毒性，从而加速结肠癌的免疫逃逸。这些发现表明 mA 靶向免疫检查点阻断在结肠癌中有潜在的应用，为结肠癌免疫逃逸和抗肿瘤免疫提供了新的见解，为进一步的精准治疗提供了依据。
