Ionic immune suppression within the tumour microenvironment limits T cell effector function.
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Authors
Eil, Robert
Vodnala, Suman K
Clever, David
Klebanoff, Christopher A
Sukumar, Madhusudhanan
Pan, Jenny H
Palmer, Douglas C
Gros, Alena
Yamamoto, Tori N
Patel, Shashank J
Guittard, Geoffrey C
Yu, Zhiya
Carbonaro, Valentina
Schrump, David S
Linehan, W Marston
Restifo, Nicholas P
Publication Date
2016-09-22Journal Title
Nature
ISSN
0028-0836
Volume
537
Issue
7621
Language
eng
Type
Article
This Version
AM
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Eil, R., Vodnala, S. K., Clever, D., Klebanoff, C. A., Sukumar, M., Pan, J. H., Palmer, D. C., et al. (2016). Ionic immune suppression within the tumour microenvironment limits T cell effector function.. Nature, 537 (7621)https://doi.org/10.1038/nature19364
Abstract
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+]e is 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+]i and 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.
Identifiers
External DOI: https://doi.org/10.1038/nature19364
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277587
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