| Summary: | <p><strong><em>Background:</em></strong> Dying tumor cells release intracellular potassium (K<sup>+</sup>), raising extracellular K<sup>+</sup> ([K<sup>+</sup>]<sub>e</sub>) in the tumor microenvironment (TME) to 40–50 mM (high-[K<sup>+</sup>]<sub>e</sub>). Here, we investigated the effect of high-[K<sup>+</sup>]<sub>e</sub> on T cell functions.</p>
<p><strong><em>Materials and Methods:</em></strong> Functional impacts of high-[K<sup>+</sup>]<sub>e</sub> on human T cells were determined by cellular, molecular, and imaging assays.</p>
<p><strong><em>Results:</em></strong> Exposure to high-[K<sup>+</sup>]<sub>e</sub> suppressed the proliferation of central memory and effector memory T cells, while T memory stem cells were unaffected. High-[K<sup>+</sup>]<sub>e</sub> inhibited T cell cytokine production and dampened antitumor cytotoxicity, by modulating the Akt signaling pathway. High-[K<sup>+</sup>]<sub>e</sub> caused significant upregulation of the immune checkpoint protein PD-1 in activated T cells. Although the number of K<sub>Ca</sub>3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K<sup>+</sup>]<sub>e</sub>, a novel K<sub>Ca</sub>3.1 activator, SKA-346, rescued T cells from high-[K<sup>+</sup>]<sub>e</sub>-mediated suppression.</p>
<p><strong><em>Conclusion:</em></strong> High-[K<sup>+</sup>]<sub>e</sub> represents a so far overlooked secondary checkpoint in cancer. K<sub>Ca</sub>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.</p>
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