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 roduction 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 KCa3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K+]e, a novel KCa3.1 activator, SKA346, rescued T cells from high-[K+]e-mediated suppression.

Conclusion: High-[K+ ]e represents a so far overlooked secondary checkpoint in cancer. KCa3.1 activators could overcome such ‘‘ionic-checkpoint’’-mediated immuno-suppression in the TME, and be administered together with known PD-1 inhibitors and other cancer therapeutics to improve outcomes.