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. 2023 Jun;53(6):e2250258.
doi: 10.1002/eji.202250258. Epub 2023 Mar 19.

Acidity-mediated induction of FoxP3+ regulatory T cells

Disha Rao  1 , Johanna A Stunnenberg  1 , Ruben Lacroix  1 , Petros Dimitriadis  1 , Joanna Kaplon  2 , Fabienne Verburg  1 , Paula T van van Royen  1 , Esmée P Hoefsmit  1 , Kathrin Renner  3   4 , Christian U Blank  1   5   6 , Daniel S Peeper  1   7
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Free article

Acidity-mediated induction of FoxP3+ regulatory T cells

Disha Rao et al. Eur J Immunol. 2023 Jun.
Free article

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.

Keywords: Lactic acid; Regulatory T cells; Treg metabolism; Tumor microenvironment.

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