Acidity-mediated induction of FoxP3+ regulatory T cells |
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Authors: | Disha Rao Johanna A. Stunnenberg Ruben Lacroix Petros Dimitriadis Joanna Kaplon Fabienne Verburg Paula T. van van Royen Esmée P. Hoefsmit Kathrin Renner Christian U. Blank Daniel S. Peeper |
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Affiliation: | 1. Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands;2. Department of Clinical Chemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands;3. Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany Department of Otorhinolaryngology, University Hospital Regensburg, Regensburg, Germany |
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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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Keywords: | Lactic acid Regulatory T cells Treg metabolism Tumor microenvironment |
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