Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity

Soll D, Chu CF, Sun S, Lutz V, Arunkumar M, Gachechiladze M, Schäuble S, Alissa-Alkhalaf M, Nguyen T, Khalil MA, Garcia-Ribelles I, Mueller M, Buder K, Michalke B, Panagiotou G, Ziegler-Martin K, Benz P, Schatzlmaier P, Hiller K, Stockinger H, Luu M, Schober K, Moosmann C, Schamel WW, Huber M, Zielinski CE (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Nature Immunology Nature Research

DOI: 10.1038/s41590-024-01918-6

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.

Authors with CRIS profile

Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Carolin Moosmann Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Technische Universität Braunschweig DE Germany (DE) Medizinische Universität Wien AT Austria (AT) Universitätsklinikum Würzburg DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie (Hans-Knöll-Institut (HKI)) / Leibniz Institute for Natural Product Research and Infection Biology DE Germany (DE) Philipps-Universität Marburg DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE)

How to cite

APA:

Soll, D., Chu, C.F., Sun, S., Lutz, V., Arunkumar, M., Gachechiladze, M.,... Zielinski, C.E. (2024). Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity. Nature Immunology. https://doi.org/10.1038/s41590-024-01918-6

MLA:

Soll, Dominik, et al. "Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity." Nature Immunology (2024).

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