Sodium Chloride in the Tumor Microenvironment Enhances T Cell Metabolic Fitness and Cytotoxicity

Overview

Journal Nat Immunol

Date 2024 Aug 28

PMID 39198632

Authors

Dominik Soll

Chang-Feng Chu

Shan Sun

Veronika Lutz

Mahima Arunkumar

Mariam Gachechiladze

Sascha Schauble

Maha Alissa-Alkhalaf

Trang Nguyen

Michelle-Amirah Khalil

Ignacio Garcia-Ribelles

Michael Mueller

Katrin Buder

Bernhard Michalke

Gianni Panagiotou

Kai Ziegler-Martin

Pascal Benz

Philipp Schatzlmaier

Karsten Hiller

Hannes Stockinger

Maik Luu

Kilian Schober

Carolin Moosmann

Wolfgang W Schamel

Magdalena Huber

Christina E Zielinski

Affiliations

Soon will be listed here.

Abstract

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.

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