Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
Dominik SollChang-Feng ChuShan SunVeronika LutzMahima ArunkumarMariam GachechiladzeSascha SchäubleMaha Alissa-AlkhalafTrang NguyenMichelle-Amirah KhalilIgnacio Garcia-RibellesMichael MuellerKatrin BuderBernhard MichalkeGianni PanagiotouKai Ziegler-MartinPascal BenzPhilipp SchatzlmaierKarsten HillerHannes StockingerMaik LuuKilian SchoberCarolin MoosmannWolfgang W SchamelMagdalena HuberChristina E ZielinskiPublished in: Nature immunology (2024)
The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8 + T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8 + T cells are linked to sodium-induced upregulation of Na + /K + -ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
Keyphrases
- high glucose
- diabetic rats
- immune response
- drug induced
- endothelial cells
- regulatory t cells
- physical activity
- body composition
- dendritic cells
- stem cells
- cell proliferation
- liver failure
- oxidative stress
- transcription factor
- intensive care unit
- signaling pathway
- cell therapy
- single molecule
- inflammatory response
- mesenchymal stem cells
- induced pluripotent stem cells
- type iii