Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K+]eis independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K+]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K+]iand improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Robert
R
Eil
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Suman K
SK
Vodnala
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
David
D
Clever
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.|Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Christopher A
CA
Klebanoff
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Madhusudhanan
M
Sukumar
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Jenny H
JH
Pan
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Douglas C
DC
Palmer
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Alena
A
Gros
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Tori N
TN
Yamamoto
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Shashank J
SJ
Patel
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Geoffrey C
GC
Guittard
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Zhiya
Z
Yu
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
Valentina
V
Carbonaro
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
Klaus
K
Okkenhaug
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
David S
DS
Schrump
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
W Marston
WM
Linehan
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
Rahul
R
Roychoudhuri
National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Nicholas P
NP
Restifo
D000818:Animals; D002414:Cations, Monovalent / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D051664:Kv1.3 Potassium Channel / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008564:Membrane Potentials; D051379:Mice; D009336:Necrosis; D011188:Potassium / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
D002414:Cations, Monovalent; D051664:Kv1.3 Potassium Channel; D011948:Receptors, Antigen, T-Cell; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011188:Potassium