Acidity‐mediated induction of FoxP3 + regulatory T cells

2023/02/14 by Disha Rao, Johanna A. Stunnenberg, Ruben Lacroix +9 · 19 citations
Immunology and Microbiology · #Bacteria #Biochemistry #Biology #Cancer research #Cell biology #Effector #Extracellular #FOXP3 #Glycolysis #IL-2 receptor #Immune Cell Function and Interaction #Immune cells in cancer #Immune system #Immunology #In vivo #Lactic acid #Metabolism #Regulatory T cell #T cell #T-cell and B-cell Immunology #Tumor microenvironment

paper · pdf · doi:10.1002/eji.202250258

openalex publication_date 2023/02/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28

Abstract

Abstract Glucose limitation and increased lactic acid levels are consequences of the elevated glycolytic activity of tumor cells, and constitute a metabolic barrier for the function of tumor infiltrating effector immune cells. The immune‐suppressive functions of regulatory T cells (Tregs) are unobstructed in lactic‐acid rich environments. However, the impact of lactic acid on the induction of Tregs remains unknown. We observed increased TGFβ‐mediated induction of Forkhead box P3 + (FoxP3 + ) cells in the presence of extracellular lactic acid, in a glycolysis‐independent, acidity‐dependent manner. These CD4 + FoxP3 + cells expressed Treg‐associated markers, including increased expression of CD39, and were capable of exerting suppressive functions. Corroborating these results in vivo, we observed that neutralizing the tumor pH by systemic administration of sodium bicarbonate (NaBi) decreased Treg abundance. We conclude that acidity augments Treg induction and propose that therapeutic targeting of acidity in the tumor microenvironment (TME) might reduce Treg‐mediated immune suppression within tumors.

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