Ionic immune suppression within the tumour microenvironment limits T cell effector function

Article

关键词: PHOSPHATASE 2A;    CANCER-IMMUNOTHERAPY;    CRITICAL REGULATOR;    MODULATION;    CHANNELS;    QUANTIFICATION;    LYMPHOCYTES;    INHIBITION;    ACTIVATION;    TARGET;   

DOI  :  10.1038/nature19364

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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