IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Apoptosis Pub Date : 2024-10-13 DOI:10.1007/s10495-024-02020-w
Kai Lin, Xiufeng Lin, Fan Luo
{"title":"IGF2BP3 boosts lactate generation to accelerate gastric cancer immune evasion","authors":"Kai Lin,&nbsp;Xiufeng Lin,&nbsp;Fan Luo","doi":"10.1007/s10495-024-02020-w","DOIUrl":null,"url":null,"abstract":"<div><p>The CD8<sup>+</sup> T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8<sup>+</sup> T cells’ antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8<sup>+</sup> T cells’ antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the m<sup>6</sup>A site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8<sup>+</sup> T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8<sup>+</sup> T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"29 11-12","pages":"2147 - 2160"},"PeriodicalIF":6.1000,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Apoptosis","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10495-024-02020-w","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The CD8+ T cells mediated antitumor immunity plays a critical function on gastric cancer (GC) immunotherapy. However, the mechanism of N6-methyladenosine (m6A) and lactate in GC immune microenvironment are still unclear. Here, present research investigated the role of Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) in GC and its in-depth mechanisms in the antitumor immunity. Data illustrated that high IGF2BP3 level was associated to GC poor prognosis and tumor infiltration. Functional assays demonstrated that IGF2BP3 overexpression could promote the lactate accumulation, and impair the CD8+ T cells’ antitumor immunity activity in co-culture system. Correspondingly, IGF2BP3 silencing enhanced the CD8+ T cells’ antitumor immunity activity towards co-cultured GC cells. Mechanistically, IGF2BP3 could bind the m6A site on LDHA mRNA, thereby promoting its mRNA stability. Rescue assays elucidated that IGF2BP3/LDHA axis impaired the CD8+ T cells antitumor immunity by triggering lactate excess tumor microenvironment. In conclusion, our findings demonstrate that IGF2BP3 impairs the CD8+ T cells antitumor immunity by targeting LDHA/lactate axis, providing a novel therapeutic insight for GC immunotherapy.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
IGF2BP3 促进乳酸生成,加速胃癌免疫逃避。
CD8+ T细胞介导的抗肿瘤免疫在胃癌(GC)免疫治疗中发挥着关键作用。然而,N6-甲基腺苷(m6A)和乳酸在胃癌免疫微环境中的作用机制尚不清楚。本研究探讨了胰岛素样生长因子II mRNA结合蛋白3(IGF2BP3)在胃癌中的作用及其在抗肿瘤免疫中的深层机制。数据显示,高水平的IGF2BP3与GC的不良预后和肿瘤浸润有关。功能试验表明,IGF2BP3过表达可促进乳酸堆积,并损害共培养系统中CD8+ T细胞的抗肿瘤免疫活性。相应地,沉默 IGF2BP3 可增强 CD8+ T 细胞对共培养 GC 细胞的抗肿瘤免疫活性。从机理上讲,IGF2BP3能与LDHA mRNA上的m6A位点结合,从而促进其mRNA的稳定性。拯救试验阐明,IGF2BP3/LDHA轴通过引发乳酸过多的肿瘤微环境,损害了CD8+ T细胞的抗肿瘤免疫力。总之,我们的研究结果表明,IGF2BP3通过靶向LDHA/乳酸轴损害了CD8+ T细胞的抗肿瘤免疫能力,为GC免疫疗法提供了新的治疗思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
期刊最新文献
Involvement of copper in cell death and cancer. Necroptosis in obesity: a complex cell death event. EFNA4-enhanced deubiquitination of SLC7A11 inhibits ferroptosis in hepatocellular carcinoma. Microglia programmed cell death in neurodegenerative diseases and CNS injury. GAS5 long non-coding RNA interacts with microRNA-205 to relieve fibroblast-like synoviocyte inflammation and ferroptosis in osteoarthritis.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1