Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma

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

doi:10.1016/j.xcrm.2024.101731

Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma

Cell Rep Med. 2024 Oct 15;5(10):101731. doi: 10.1016/j.xcrm.2024.101731. Epub 2024 Sep 19.

Authors

Lihong He¹, Xiaozhen Zhang¹, Fukang Shi², Hanjia Zhang², Yan Chen², Kang Sun², Hanshen Yang², Jiatao Shi², Zihao Lin², Qingsong Lu², Sicheng Wang², Linyue Liu², Xinyuan Liu², Qingbo Meng², Junmin Huang², Pinglong Xu³, Xueli Bai⁴, Tingbo Liang⁵

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, Zhejiang, China.
² Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
³ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China; Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, Zhejiang, China.
⁴ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, Zhejiang, China. Electronic address: shirleybai@zju.edu.cn.
⁵ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China; MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, Zhejiang, China. Electronic address: liangtingbo@zju.edu.cn.

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.

Keywords: eIF4G1; immunotherapy; integrinβ1; translation regulation; tumor fibrosis; tumor microenvironment.

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / immunology
Carcinoma, Pancreatic Ductal* / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Deoxycytidine / therapeutic use
Eukaryotic Initiation Factor-4G* / metabolism
Gemcitabine
Humans
Integrin beta1 / genetics
Integrin beta1 / metabolism
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / metabolism
Pancreatic Neoplasms* / pathology
Signal Transduction
T-Lymphocytes, Cytotoxic / immunology
Tumor Microenvironment* / immunology

Substances

Eukaryotic Initiation Factor-4G
EIF4G1 protein, human
Deoxycytidine
Integrin beta1
Gemcitabine