Repercussions of high extracellular K +on T-cell antitumor responses

Abstract

Abstract Tumours create an immunosuppressive microenvironment that limits the antitumor function of infiltrating T-cells. Dying/necrotic tumor cells extrude intracellular potassium (K +) into the local extracellular milieu, raising the extracellular K +([K +] e) by 8–15 fold, which then accumulates in tumor-infiltrating T-cells. Here, we determined the functional impact of high-[K +] e(50 mM) on human T-cells. Using molecular assays, we demonstrated that prolonged exposure to high-[K +] ereduced CD3ɛ and CD25 (intermediate activation marker) surface expression, suggesting weakened T-cell activation. High-[K +] eperturbed T-cell receptor signalling and the downstream glycolysis pathway. Using metabolomics analysis, we identified dysregulation in pathways involving fatty acid oxidation, TCA cycle and choline metabolism under high-[K +] e. Exposure to high-[K +] eimpeded T-cell motility and skewed T-cell polarization towards T-helper 2 (Th2) and regulatory T-cell (T reg) subsets. A similar Th2 subset trend, although not significant, was seen towards the core of patient-derived tumor biopsies (n=7) along with the amassment of T regcells intratumorally. Collectively, our findings substantiate the immunosuppressive effects of high-[K +] eon T-cell functions, which underlines the potential use of K +efflux channel activators in reversing dampened T-cell antitumor responses. Supported by Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 1 Grant (2020-T1-001-062) and Tier 2 (MOE2017-T2-2-004) grants. #LINK# #ENDLINK#