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




Seow Theng Ong, Aik Seng Ng, Xuan Rui Ng, Zhong Zhuang, Brandon Han Siang Wong, Praseetha Prasannan, Yee Jiun Kok, Xuezhi Bi, Heesung Shim, Heike Wulff, Kanianthara George Chandy, and Navin Kumar Verma



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.

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