Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy

IF 27.7 1区 医学 Q1 IMMUNOLOGY Nature Immunology Pub Date : 2024-09-26 DOI:10.1038/s41590-024-01963-1
Geoffrey J. Markowitz, Yi Ban, Diamile A. Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T. Martin, Michael J. P. Crowley, Tito A. Sandoval, Dingcheng Gao, M. Laura Martin, Olivier Elemento, Juan R. Cubillos-Ruiz, Timothy E. McGraw, Nasser K. Altorki, Vivek Mittal
{"title":"Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy","authors":"Geoffrey J. Markowitz, Yi Ban, Diamile A. Tavarez, Liron Yoffe, Enrique Podaza, Yongfeng He, Mitchell T. Martin, Michael J. P. Crowley, Tito A. Sandoval, Dingcheng Gao, M. Laura Martin, Olivier Elemento, Juan R. Cubillos-Ruiz, Timothy E. McGraw, Nasser K. Altorki, Vivek Mittal","doi":"10.1038/s41590-024-01963-1","DOIUrl":null,"url":null,"abstract":"TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy. TCF1+ progenitor-exhausted CD8+ T cell populations mediate durable antitumor immunity. Upon antigenic stimulation, effector T cells upregulate aerobic glycolysis to support their cytotoxic phenotype. Here, Mittal and colleagues find that loss of metabolic regulator PKM2 enriches for TCF1+ progenitor-exhausted-like cells and improves responsiveness to PD-1 blockade.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":"25 10","pages":"1884-1899"},"PeriodicalIF":27.7000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-01963-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy. TCF1+ progenitor-exhausted CD8+ T cell populations mediate durable antitumor immunity. Upon antigenic stimulation, effector T cells upregulate aerobic glycolysis to support their cytotoxic phenotype. Here, Mittal and colleagues find that loss of metabolic regulator PKM2 enriches for TCF1+ progenitor-exhausted-like cells and improves responsiveness to PD-1 blockade.

Abstract Image

Abstract Image

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
代谢调节因子 PKM2 的缺乏会激活磷酸戊糖通路并产生 TCF1+ 祖 CD8+ T 细胞,从而改善免疫疗法
TCF1高的祖CD8+ T细胞可介导免疫疗法的疗效;然而,人们对其产生和维持的机制知之甚少。在这里,我们发现通过删除丙酮酸激酶肌2(PKM2)来靶向糖酵解会导致磷酸戊糖途径(PPP)活性升高,从而富集类似TCF1高祖细胞耗竭的表型,并增加体内对PD-1阻断的反应性。PKM2KO CD8+ T细胞显示出糖酵解通量降低、糖酵解中间产物和PPP代谢产物积累以及1,2-13C葡萄糖碳追踪测定的PPP循环增加。在没有急性糖酵解损伤的情况下,小分子激动剂激动 PPP 可使 CD8+ T 细胞向 TCF1 高的群体倾斜,产生独特的转录景观,激动剂处理过的 CD8+ T 细胞与 PD-1 阻断联合应用可增强对小鼠肿瘤的控制,并促进患者来源的肿瘤组织细胞对肿瘤的杀伤。我们的研究证明了一种新的代谢重编程,有助于形成一种促进免疫疗法疗效的祖细胞样 T 细胞状态。
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
Nature Immunology
Nature Immunology 医学-免疫学
CiteScore
40.00
自引率
2.30%
发文量
248
审稿时长
4-8 weeks
期刊介绍: Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
期刊最新文献
Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells Pyroptotic corpses are flagged by filopodia to alert dendritic cells Pyroptotic cell corpses are crowned with F-actin-rich filopodia that engage CLEC9A signaling in incoming dendritic cells Author Correction: Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment Publisher Correction: Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE
×
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