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Science. 2019 Mar 29;363(6434). pii: eaau0135. doi: 10.1126/science.aau0135.

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

Author information

1
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
2
Center for Cell-Based Therapy, National Cancer Institute, Bethesda, MD 20892, USA.
3
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.
6
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
7
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27710, USA.
8
Babraham Institute, Babraham Research Campus, Cambridge, UK.
9
Aging Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
10
Parker Institute for Cancer Immunotherapy, New York, NY 10065, USA.
11
Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
12
Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
13
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. restifon@mail.nih.gov.

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.

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PMID:
30923193
DOI:
10.1126/science.aau0135
[Indexed for MEDLINE]

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