Tumor‐derived lactic acid promotes acetylation of histone <scp>H3K27</scp> and differentiation of <scp>IL</scp>‐10‐producing regulatory B cells through direct and indirect signaling pathways

Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity.