Extracellular K+ Dampens T Cell Functions: Implications for Immune Suppression in the Tumor Microenvironment.
Bioelectricity
; 1(3): 169-179, 2019 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-34471819
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 andMethods:
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.
Texto completo:
1
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article