High Extracellular K⁺ Skews T-Cell Differentiation Towards Tumour Promoting Th2 and T_reg Subsets

Area of Science:

• Immunology
• Cancer Biology
• Cellular Physiology

Background:

• Dying tumor cells release potassium ions (K+), increasing extracellular K+ concentration ([K+]e) in the tumor microenvironment (TME).
• Elevated [K+]e is implicated in the immunosuppressive TME, but its direct impact on T-cell function is not fully elucidated.

Purpose of the Study:

• To investigate the effects of high extracellular potassium ([K+]e) on T-cell receptor signaling, metabolism, and differentiation.
• To understand how [K+]e contributes to the immunosuppressive TME in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC).

Main Methods:

• Analysis of T-cell receptor subunit expression (CD3ε, CD3ζ) and co-stimulatory receptor CD28.
• Assessment of T-cell metabolic profiles, including glucose and glutamine metabolism.
• Flow cytometry and GeoMx digital spatial profiling to analyze T-cell phenotypes in tumor tissues.

Main Results:

• High [K+]e significantly decreased CD3ε, CD3ζ, and CD28 expression on T-cells.
• Elevated [K+]e altered T-cell metabolism, limiting glucose and glutamine utilization, indicative of functional exhaustion.
• High [K+]e skewed T-cell differentiation towards tumor-promoting Th2 and regulatory T (iTreg) cells, while suppressing anti-tumor Th1 and Th17 cells.

Conclusions:

• High extracellular potassium concentration is a key factor dysregulating T-cell function and promoting an immunosuppressive tumor microenvironment.
• These findings reveal a novel mechanism by which tumor cell death contributes to immune evasion and tumor progression.
• Targeting extracellular potassium levels could represent a potential therapeutic strategy to enhance anti-tumor immunity.