Abstract 3131: High levels of potassium impair myeloid-derived suppressor cell functions

Abstract

Abstract Excess salt consumption has been associated with elevated blood pressure, cardiovascular disease, obesity, diabetes, fatty liver, chronic inflammation, cancer, and autoimmune diseases. The direct impact of salts on immune cells is poorly studied; however, a recent report showed that a higher level of both sodium and potassium in the tumor microenvironment reduce tumor growth by enhancing T cell function. Separately, it was shown that intake of high levels of sodium reduced tumor growth by impairing myeloid-derived suppressor cell (MDSC) functions. Still, the effect of high levels of potassium on MDSCs has not been examined. Here, we hypothesize that an excess of potassium in an in-vitro culture of mouse bone marrow-derived MDSC (mBM-MDSC) and purified tumor-derived MDSC impairs the cellular metabolism and their immunosuppressive function. To explore this, we evaluated the effect of potassium (40 mM) on the oxygen consumption rate (OCR) as a measurement of mitochondrial oxidative phosphorylation (OXPHOS). We also tested the immunosuppressive function of MDSCs by protein expression of arginase I (ArgI), inducible nitric oxide synthase (iNOS), and the immune checkpoint PD-L1 on mBM-MDSC, as well as directly measuring their ability to inhibit T cell proliferation. While excess potassium does not influence the proliferation or viability of mBM-MDSCs, it does affect their immunosuppressive capacity by reducing ArgI, iNOS and PD-L1 expression. Furthermore, excess potassium increases the expression levels of the autophagosome marker LC3β, enhances OCR (an indicator of mitochondrial respiration), and improves the fitness of mitochondrial bioenergetics (maximum respiratory capacity). Interestingly, using the autophagy inhibitor 3-methyladenine (3-MA) in the presence of excess of potassium significantly reduces OCR and rescues ArgI expression compared to control or potassium treatment alone. Additionally, potassium significantly reduced the production of several chemokines and anti-inflammatory cytokines, including CXCL1, RANTES and IL-10, as well as the expression levels of C/EBP-β and phosphorylated AMPK, suggesting an alteration of key signaling pathways required for MDSC function. Collectively, this study provides evidence that high levels of potassium change the cellular metabolism of MDSC, reduce their immunosuppressive capacity, impair the signaling of AMPK, C/EBP-β, and promote autophagy. This may provide novel insights for further investigation on the impact of hyperkalemia or microenvironments with increased levels of potassium, such as intratumorally, on MDSCs and their role on tumor growth. Citation Format: Ramesh Thylur Puttalingaiah, Augusto C. Ochoa, Maria Dulfary Sanchez-Pino. High levels of potassium impair myeloid-derived suppressor cell functions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3131.