T cell stemness and dysfunction in tumors are triggered by a common mechanism

Suman Kumar Vodnala, Robert Eil, Rigel J. Kishton, Madhusudhanan Sukumar, Tori N. Yamamoto, Ngoc Han 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

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaau0135
JournalScience
Volume363
Issue number6434
DOIs
StatePublished - Mar 29 2019
Externally publishedYes

ASJC Scopus subject areas

  • General

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