High Extracellular K+ Drives T-Cell Exhaustion by Disrupting TCR Signals Implicated in Tumor Immune Evasion

Background: Tumours create an immunosuppressive microenvironment that limits the antitumor function of infiltrating T-cells. In particular, K+ ions released from dying necrotic tumour cells accumulate in the tumour microenvironment and increase the local K+ concentration to 50 mM (high-[K+]e). This study aims to investigate functional impact of high- [K+]e on human T-cells. Results: We demonstrate that high-[K+]e decreases expression of the T-cell receptor (TCR) complex and costimulatory molecule CD28, and suppresses key activation molecules, thereby dysregulating TCR-mediated signalling. High-[K+30 ]e also alters the metabolic profile of T-cells, limiting metabolism of glucose and glutamine, consistent with functional exhaustion. These changes skew T-cell differentiation, favouring Th2 and Treg subsets that promote tumour growth while restricting anti-tumour Th1 and Th17 subsets. Conclusions: Findings presented here reveal an important role of high-[K+]e in disrupting TCR signals and driving T-cell exhaustion implicated in the immunosuppressive milieu in the tumour microenvironment.