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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.
摘要
抗肿瘤免疫的有效性与细胞毒性 T 细胞的代谢状态有关，而细胞毒性 T 细胞的代谢状态对肿瘤微环境非常敏感。离子信号是否会影响适应性抗肿瘤免疫反应尚不清楚。在本研究中，我们发现乳腺癌患者的实体瘤中富含钠。氯化钠（NaCl）能增强人类 CD8+ T 细胞的活化状态和效应功能，这与新陈代谢能力增强有关。这些氯化钠诱导的效应可转化为体外和体内肿瘤细胞杀伤力的增强。从机理上讲，NaCl 诱导的 CD8+ T 细胞变化与钠诱导的 Na+/K+-ATP 酶活性上调有关，其次是膜超极化，这放大了 T 细胞受体（TCR）诱导的钙离子流入和下游 TCR 信号传导的电动力。因此，我们提出，NaCl 是急性抗肿瘤免疫的正向调节因子，可用于体内外治疗性 T 细胞（如 CAR T 细胞）的调节。
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参考文献
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. Sodium
chloride in the tumor microenvironment enhances T cell metabolic fitness
and cytotoxicity. Nat Immunol. 2024 Aug 28. doi:
10.1038/s41590-024-01918-6.
