Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Cells. 2024 Oct 19;13(20):1736. doi: 10.3390/cells13201736.
Potassium ions (K) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K ion-rich TME, which has important implications for MDSCs-targeted therapies.
钾离子（K）是调节免疫细胞多种功能的关键电解质。最近的研究表明，肿瘤间质液中细胞外钾浓度的升高限制了 T 细胞效应功能，并抑制了肿瘤相关巨噬细胞（TAMs）的抗肿瘤能力。过多的钾对髓系来源的抑制细胞（MDSCs）生物学的影响，MDSCs 是肿瘤微环境（TME）中另一种重要的免疫细胞成分，目前尚不清楚。在这里，我们提供的数据表明，增加氯化钾（KCl）的浓度作为 K 离子的来源，通过增加自噬体标记物 LC3β的表达来促进自噬。同时，过量的钾离子显著降低了精氨酸酶 I（Arg I）和诱导型一氧化氮合酶（iNOS）的表达，而不降低 MDSC 抑制 T 细胞增殖的能力。进一步的研究表明，过量的 K 离子会降低转录因子 C/EBP-β的表达，并改变磷酸化激酶的表达。虽然过量的 K 离子下调了磷酸化 AMPKα（pAMPKα）的表达水平，但增加了 pAKT 和 pERK 的水平。此外，钾离子通过耗氧量（OCR）增加了线粒体呼吸。有趣的是，K 离子引起的所有这些变化都被自噬抑制剂 3-甲基腺嘌呤（3-MA）所消除。我们的结果表明，过量 K 离子引起的高渗应激调节 MDSC 中的线粒体呼吸和信号通路，通过独立于 Arg I 和 iNOS 的机制触发自噬过程，以支持 MDSC 的免疫抑制功能。总之，我们的体外和体内研究结果提供了关于 MDSC 在富含 K 离子的 TME 中的适应的有价值的见解，这对 MDSC 靶向治疗具有重要意义。
