Functional impact of high extracellular potassium ion on human T-cells

Abstract

Despite the clinical success of current immunotherapies, there remains a pressing need to fully exploit the power of such treatments and improve their efficacy. Tumor microenvironment (TME) crucially dictates the T-cell anti-tumor immune responses. Yet, individual factors in the TME that drive immune suppression remains to be fully elucidated. Dying/necrotic tumor cells release a substantial amount of intracellular potassium ion ([K+]i), increasing extracellular potassium ion ([K+]e) to 5-10 fold. Here, we investigated the effects of high-[K+]e on the mechanistic and functional aspects of T-cells. We demonstrated via imaging, real-time impedance-based measurements and molecular assays that high-[K+]e impedes T-cell motility (15% inhibition) and possesses a chemotactic influence over T-cells. Moreover, High-[K+]e upregulates the expression of Kv1.3 K+ channel as well as PD-1 in T-cells. Using Jurkat T-cell line as a model, we observed that high-[K+]e reduces T-cell cytokines (IL-2 and IFN-𝛾) production and modulates both AMPK𝛼 and ACC expression and phosphorylation, which are prerequisite factors in cellular metabolism. Taken together, high-[K+]einduced impairment of T-cell functions reported in the current study has implications in T-cell anti-tumor immune responses and immunotherapies.