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

Background: 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. Materials and Methods: Functional impacts of high-[K+](e) on human T cells were determined by cellular, molecular, and imaging assays. Results: 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(Ca)3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K+](e), a novel K(Ca)3.1 activator, SKA-346, rescued T cells from high-[K+](e)-mediated suppression. Conclusion: High-[K+](e) represents a so far overlooked secondary checkpoint in cancer. K(Ca)3.1 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.