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, Navin Kumar Verma

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 KCa3.1 calcium-activated potassium channels expressed in T cells remained unaffected under high-[K+]e, a novel KCa3.1 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. KCa3.1 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.

Original languageEnglish (US)
Pages (from-to)169-179
Number of pages11
JournalBioelectricity
Volume1
Issue number3
DOIs
StatePublished - Sep 2019

Keywords

  • antitumor immunity
  • extracellular K
  • K3.1
  • potassium channels
  • T lymphocytes

ASJC Scopus subject areas

  • Biomedical Engineering
  • Electrical and Electronic Engineering
  • Medicine (miscellaneous)
  • Transplantation

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