Extracellular K ⁺ Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment

Abstract

<b><i>Background:</i></b> Dying tumor cells release intracellular potassium (K⁺), raising extracellular K⁺ ([K⁺]_e) in the tumor microenvironment (TME) to 40-50 mM (high-[K⁺]_e). Here, we investigated the effect of high-[K⁺]_e on T cell functions. <b><i>Materials and Methods:</i></b> Functional impacts of high-[K⁺]_e on human T cells were determined by cellular, molecular, and imaging assays. <b><i>Results:</i></b> Exposure to high-[K⁺]_e suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K⁺]_e inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K⁺]_e caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K_Ca3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K⁺]_e, a novel K_Ca3.1 activator, SKA-346, rescued T cells from high-[K⁺]_e-mediated suppression. <b><i>Conclusion:</i></b> High-[K⁺]_e represents a so far overlooked secondary checkpoint in cancer. K_Ca3.1 activators could overcome such "ionic-checkpoint"-mediated immunosuppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.