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Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Nature 2016 September 23
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 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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