效应器
生物
肿瘤微环境
癌症研究
细胞生物学
T细胞
CD8型
干细胞
免疫疗法
细胞
免疫学
免疫系统
肿瘤细胞
遗传学
作者
Suman K. Vodnala,Robert L. Eil,Rigel J. Kishton,Madhusudhanan Sukumar,Tori N. Yamamoto,Ngoc T Ha,Ping-Hsien Lee,Min Hwa Shin,Shashank J. Patel,Zhiya Yu,Douglas C. Palmer,Michael J. Kruhlak,Xiaojing Liu,Jason W. Locasale,Jing Huang,Rahul Roychoudhuri,Toren Finkel,Christopher A. Klebanoff,Nicholas P. Restifo
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2019-03-29
卷期号:363 (6434)
被引量:301
标识
DOI:10.1126/science.aau0135
摘要
A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell-like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8+ T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.
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