Targeting tumour-intrinsic N7-methylguanosine tRNA modification inhibits MDSC recruitment and improves anti-PD-1 efficacy

癌症研究 体内 肿瘤微环境 免疫系统 趋化因子 条件基因敲除 基因剔除小鼠 基因敲除 人口 生物 化学 免疫学 医学 细胞培养 受体 生物化学 表型 基因 生物技术 环境卫生 遗传学
作者
Hai‐Ning Liu,Xuezhen Zeng,Xuxin Ren,Yifan Zhang,Manling Huang,Li Tan,Zihao Dai,Jiaming Lai,Wenxuan Xie,Zebin Chen,Sui Peng,Lixia Xu,Shuling Chen,Shunli Shen,Ming Kuang,Shuibin Lin
出处
期刊:Gut [BMJ]
卷期号:72 (8): 1555-1567 被引量:35
标识
DOI:10.1136/gutjnl-2022-327230
摘要

Objective Intrahepatic cholangiocarcinoma (ICC) exhibits very low response rate to immune checkpoint inhibitors (ICIs) and the underlying mechanism is largely unknown. We investigate the tumour immune microenvironment (TIME) of ICCs and the underlying regulatory mechanisms with the aim of developing new target to inhibit tumour growth and improve anti-programmed cell death protein-1 (PD-1) efficacy. Design Tumour tissues from patients with ICC together with hydrodynamic ICC mouse models were employed to identify the key cell population in TIME of ICCs. Functional analysis and mechanism studies were performed using cell culture, conditional knockout mouse model and hydrodynamic transfection ICC model. The efficacy of single or combined therapy with anti-PD-1 antibody, gene knockout and chemical inhibitor were evaluated in vivo. Results Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are enriched in advanced ICCs and significantly correlated with N 7 -methylguanosine tRNA methyltransferase METTL1. Using diverse in vivo cancer models, we demonstrate the crucial immunomodulator function of METTL1 in regulation of PMN-MDSC accumulation in TIME and ICC progression. Mechanistically, CXCL8 in human and Cxcl5 in mouse are key translational targets of METTL1 that facilitate its function in promoting PMN-MDSC accumulation in TIME and ICC progression in vivo. Co-blockade of METTL1 and its downstream chemokine pathway enhances the anti-PD-1 efficacy in ICC preclinical mouse models. Conclusions Our data uncover novel mechanisms underlying chemokine regulation and TIME shaping at the layer of messenger RNA translation level and provide new insights for development of efficient cancer immunotherapeutic strategies.
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