Journal
NATURE
Volume 537, Issue 7621, Pages 539-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature19364
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Funding
- NCI
- Wellcome Trust/Royal Society [105663/Z/14/Z]
- UK Biotechnology and Biological Sciences Research Council [BB/N007794/1]
- Biotechnology and Biological Sciences Research Council [BB/N007794/1, BBS/E/B/000C0407] Funding Source: researchfish
- Cancer Research UK [S_3402] Funding Source: researchfish
- Wellcome Trust [105663/Z/14/Z] Funding Source: Wellcome Trust
- BBSRC [BB/N007794/1, 1642652, BBS/E/B/000C0407] Funding Source: UKRI
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Tumours progress despite being infiltrated by tumour-specific effector T cells(1). Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers(2). 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(3,4). Although the suppressive effect mediated by elevated [K+](e) is independent of changes in plasma membrane potential (V-m), it requires an increase in intracellular potassium ([K+](i)). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv(1.3) 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.
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