Soll, Chu, and Sun et al. demonstrated increased intratumoral Na+ ion concentrations and enrichment of an NaCl gene signature in solid tumors from patients with breast cancer. High NaCl concentration augmented nutrient uptake and metabolic reprogramming to potentiate activation and cytotoxic effector functions of human CD8+ T cells. Mechanistically, NaCl upregulated Na+/K+-ATPase activity, membrane hyperpolarization, calcium influx, and downstream TCR signaling, leading to enhanced cytotoxicity. Stimulation of CAR T cells or TCR-engineered T cells under high NaCl conditions increased tumor cell killing in vitro and in vivo in the PancOVA model.
Contributed by Shishir Pant
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.
Author Info: (1) Technical University of Munich, Munich, Germany. (2) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Instit
Author Info: (1) Technical University of Munich, Munich, Germany. (2) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (3) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (4) Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany. (5) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (6) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (7) Department of Microbiome Dynamics, Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (8) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (9) Institute of Biology III, Faculty of Biology and Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency, University Clinics and Medical Faculty, University of Freiburg, Freiburg, Germany. Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany. (10) Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology, Technical University of Braunschweig, Braunschweig, Germany. (11) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (12) Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. (13) Leibniz Institute for Aging, Jena, Germany. (14) Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich-German Research Center for Environmental Health (GmbH), Neuherberg, Germany. (15) Department of Microbiome Dynamics, Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. Jena University Hospital, Friedrich Schiller University, Jena, Germany. (16) Chair for Cellular Immunotherapy, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. (17) Chair for Cellular Immunotherapy, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. (18) Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, Austria. (19) Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology, Technical University of Braunschweig, Braunschweig, Germany. (20) Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Vienna, Austria. (21) Chair for Cellular Immunotherapy, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany. (22) Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany. FAU Profile Center Immunomedicine, FAU Erlangen-Nürnberg, Erlangen, Germany. (23) Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany. (24) Institute of Biology III, Faculty of Biology and Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Center of Chronic Immunodeficiency, University Clinics and Medical Faculty, University of Freiburg, Freiburg, Germany. (25) Institute of Systems Immunology, Philipps-University Marburg, Marburg, Germany. (26) Technical University of Munich, Munich, Germany. christina.zielinski@uni-jena.de. Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany. christina.zielinski@uni-jena.de. Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University Jena, Jena, Germany. christina.zielinski@uni-jena.de.
