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

Dying tumor cells release intracellular potassium (K), raising extracellular K ([K]) in the tumor microenvironment (TME) to 40-50 mM (high-[K]). Here, we investigated the effect of high-[K] on T cell functions. Functional impacts of high-[K] on human T cells were determined by cellular, molecular, and imaging assays. Exposure to high-[K] suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K] inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K] caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K], a novel K3.1 activator, SKA-346, rescued T cells from high-[K]-mediated suppression. High-[K] represents a so far overlooked secondary checkpoint in cancer. K3.1 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.