SCI

16 September 2024

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

(Nature Immunology, IF: 27.7)

  • Dominik Soll, Chang-Feng Chu, Shan Sun, Veronika Lutz, Mahima Arunkumar, Mariam Gachechiladze, Sascha Sch.uble, Maha Alissa-Alkhalaf, Trang Nguyen, Michelle-Amirah Khalil8, Ignacio Garcia-Ribelles2, Michael Mueller2, Katrin Buder9, Bernhard Michalke10, Gianni Panagiotou4,11, Kai Ziegler-Martin12, Pascal Benz12, Philipp Schatzlmaier13, Karsten Hiller8, Hannes Stockinger13, Maik Luu12, Kilian Schober14,15, Carolin Moosmann14, Wolfgang W. Schamel5,6, Magdalena Huber3 & Christina E. Zielinski

  • CORRESPONDENCE TO：christina.zielinski@uni-jena.de

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.

抗肿瘤免疫的疗效与细胞毒性T细胞的代谢状态有关，细胞毒性T淋巴细胞对肿瘤微环境敏感。离子信号是否影响适应性抗肿瘤免疫反应尚不清楚。在本研究中，我们发现癌症患者的实体瘤中存在钠富集。氯化钠（NaCl）增强人 CD 8+ T细胞的活化状态和效应器功能，这与增强代谢适应性有关。这些NaCl诱导的效应转化为体外和体内肿瘤细胞杀伤的增加。从机制上讲，NaCl诱导的 CD 8+ T细胞变化与钠诱导的Na+/K+-ATP酶活性上调有关，随后是膜超极化，这放大了T细胞受体（TCR）诱导的钙内流和下游TCR信号传导的电动势。因此，我们提出NaCl是急性抗肿瘤免疫的正调节因子，可被用于治疗性T细胞（如CAR T细胞）的离体调节。


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