How the Potassium Channel Response of T Lymphocytes to the Tumor Microenvironment Shapes Antitumor Immunity

Abstract

Competent antitumor immune cells are fundamental for tumor surveillance and combating active cancers. Once established, tumors generate a tumor microenvironment (TME) consisting of complex cellular and metabolic elements that serve to suppress the function of antitumor immune cells. T lymphocytes are key cellular elements of the TME. In this review, we explore the role of ion channels, particularly K+ channels, in mediating the suppressive effects of the TME on T cells. First, we will review the complex network of ion channels that mediate Ca2+ influx and control effector functions in T cells. Then, we will discuss how multiple features of the TME influence the antitumor capabilities of T cells via ion channels. We will focus on hypoxia, adenosine, and ionic imbalances in the TME, as well as overexpression of programmed cell death ligand 1 by cancer cells that either suppress K+ channels in T cells and/or benefit from regulating these channels’ activity, ultimately shaping the immune response. Finally, we will review some of the cancer treatment implications related to ion channels. A better understanding of the effects of the TME on ion channels in T lymphocytes could promote the development of more effective immunotherapies, especially for resistant solid malignancies.

High Extracellular K+ Drives T-Cell Exhaustion by Disrupting TCR Signals Implicated in Tumor Immune Evasion

“…Entry of K + into TILs in the TME is facilitated by Na + /K + ATPase. CRISPR-Cas9-mediated disruption of the Atp1a1 gene that encodes Na + /K + ATPase decreases intracellular K + in mouse and human CD8 + T-cells [40]. Exit of K + from TILs is through two K + channels, KV1.3 and KCa3.1 [41].…”

Exploring the therapeutic opportunities of potassium channels for the treatment of rheumatoid arthritis

“…Moreover, in T lymphocytes, ion channels have a prominent role in maintaining calcium levels, which are crucial for the proliferation and effector functions of cells ( Cahalan and Chandy, 2009 ). In human T cells, Kv1.3 and KCa3.1 are the principal potassium channels that are important for maintaining the electrochemical driving force ( Chirra et al, 2022 ). The voltage-gated Kv1.3 channel in T cells gets activated by calcium influx mediated by the calcium release-activated channels (CRACs), while the increase in Ca 2+ activates KCa3.1, which causes efflux of K + ions, thereby maintaining the membrane potential and driving force for the influx of Ca 2+ , as represented in Figure 2 ( Teisseyre et al, 2019 ; Chirra et al, 2022 ).…”

“…In human T cells, Kv1.3 and KCa3.1 are the principal potassium channels that are important for maintaining the electrochemical driving force ( Chirra et al, 2022 ). The voltage-gated Kv1.3 channel in T cells gets activated by calcium influx mediated by the calcium release-activated channels (CRACs), while the increase in Ca 2+ activates KCa3.1, which causes efflux of K + ions, thereby maintaining the membrane potential and driving force for the influx of Ca 2+ , as represented in Figure 2 ( Teisseyre et al, 2019 ; Chirra et al, 2022 ). The expression, function, and role of the K + channel vary as per the activation status and subset of T cells ( Beeton and Chandy, 2005 ; Pérez-García et al, 2018 ).…”

“…As such, there is no direct link between the mutations of potassium channels with RA pathogenesis. The primary potassium channels in human T cells, such as Kv1.3 and KCa3.1, play a crucial role in maintaining the ionic levels necessary for the healthy operation of T cells and the immunological response ( Chirra et al, 2022 ). Studies identified that potassium channels regulate the immune cell function and control the RA-fibroblast-like synoviocyte (FLS) function, which is important in the pathogenesis of RA ( Hu et al, 2012 ).…”

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

“…The ratio of the number of Kv1.3 to KCa3.1 channels in T cells depends on the phenotype that the T cells acquire after their activation ( Cahalan and Chandy, 2009 ). The operation of the Kv1.3 and KCa3.1 channels is crucial for the maintenance of a permissive membrane potential for efficient Ca 2+ signaling required for T cell activation and proliferation ( Cahalan and Chandy, 2009 ), Chirra et al, reviewed and thoroughly analyzed recently how much the activity of K + channels influence the survival of T cells, their cytokine production and their motility ( Chirra et al, 2022 ).…”