Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-09-19 DOI:10.1016/j.xcrm.2024.101731

Lihong He, Xiaozhen Zhang, Fukang Shi, Hanjia Zhang, Yan Chen, Kang Sun, Hanshen Yang, Jiatao Shi, Zihao Lin, Qingsong Lu, Sicheng Wang, Linyue Liu, Xinyuan Liu, Qingbo Meng, Junmin Huang, Pinglong Xu, Xueli Bai, Tingbo Liang

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Abstract

Current therapies against pancreatic ductal adenocarcinoma (PDAC) have limited clinical benefits owing to tumor heterogeneity and their unique immunosuppressive microenvironments. The eukaryotic initiation factor (eIF) 4F complex is involved in regulating translation and various downstream carcinogenic signaling pathways. We report that eIF4G1, one of the subunits of eIF4F, is overexpressed in cancer cells and cancer-associated fibroblasts, and this correlates with poor prognosis in patients with PDAC. In PDAC mice, eIF4G1 inhibition limits tumor progression and prolongs overall survival, especially when combined with PD1/PDL1 antagonists and gemcitabine. Mechanistically, eIF4G1 inhibition hinders the production of cytokines and chemokines that promote fibrosis and inhibit cytotoxic T cell chemotaxis. Moreover, eIF4G1 inhibition impairs integrinβ1 protein translation and exerts tumor suppression effects through the FAK-ERK/AKT signaling pathway. These findings highlight the effects of eIF4G1 on tumor immune dependence and independence and identify eIF4G1 as a promising therapeutic target for PDAC.

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以 eIF4G1 为靶点重编程免疫抑制微环境，根除胰腺导管腺癌

由于肿瘤的异质性及其独特的免疫抑制微环境，目前针对胰腺导管腺癌（PDAC）的疗法临床疗效有限。真核起始因子（eIF）4F复合物参与调节翻译和各种下游致癌信号通路。我们报告说，eIF4F 的亚基之一 eIF4G1 在癌细胞和癌相关成纤维细胞中过表达，这与 PDAC 患者的不良预后相关。在 PDAC 小鼠中，抑制 eIF4G1 可限制肿瘤进展并延长总生存期，尤其是与 PD1/PDL1 拮抗剂和吉西他滨联合使用时。从机理上讲，eIF4G1抑制剂会阻碍细胞因子和趋化因子的产生，而细胞因子和趋化因子会促进纤维化并抑制细胞毒性T细胞趋化。此外，抑制 eIF4G1 还会影响整合素β1 蛋白的翻译，并通过 FAK-ERK/AKT 信号通路发挥抑制肿瘤的作用。这些发现强调了eIF4G1对肿瘤免疫依赖性和独立性的影响，并将eIF4G1确定为治疗PDAC的一个有前景的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.