Helicobacter pylori activates histone lactylation to promote gastric cancer progression and immune evasion through the HAS2/c-MYC/PD-L1 axis.
Metabolic reprogramming and epigenetic alterations play important roles in driving tumor microenvironment (TME) remodeling and immune evasion in gastric cancer (GC). Histone lactylation links glycolytic metabolism to transcriptional regulation, but its role in Helicobacter pylori (H. pylori)-associated GC progression remains largely elusive.
Multiomics analysis (ChIP-seq and RNA-seq) with in vitro GC/CD8+ T-cell coculture systems and in vivo mouse xenograft models were employed in this study. Clinical GC tissue cohorts were analyzed to validate the clinical relevance of the identified signaling pathways. The epigenetic and immunological impacts of lactate metabolism were assessed using glycolysis inhibitors (2-DG and oxamate) and genetic silencing of LDHA and LDHB.
Histone lactylation, specifically H3K18la, was significantly elevated in GC tissues and further elevated upon H. pylori infection. Pharmacological inhibition of glycolysis or LDHA/B double knockdown (DKD) markedly reduced H3K18la levels, suppressed GC cell proliferation, and restored CD8+ T cell-mediated cytotoxicity. Mechanistically, H3K18la directly bound to the HAS2 promoter, transcriptionally activating its expression. Upregulated HAS2 facilitated the nuclear translocation of c-MYC, which subsequently bound to the CD274 promoter to induce PD-L1 expression. Furthermore, c-MYC overexpression rescued PD-L1 levels and reversed the restored CD8+ T-cell cytotoxicity in LDHA/B-deficient GC cells. In vivo, the combination of oxamate and anti-PD-1 blockade synergistically enhanced CD8+ T-cell infiltration and exerted robust antitumor efficacy.
H. pylori-associated lactate-driven H3K18la promotes GC progression and immune evasion through the HAS2/c-MYC/PD-L1 axis. These findings provide preclinical support for combining metabolic inhibition with PD-1 blockade in GC, particularly in H. pylori-associated disease.
Multiomics analysis (ChIP-seq and RNA-seq) with in vitro GC/CD8+ T-cell coculture systems and in vivo mouse xenograft models were employed in this study. Clinical GC tissue cohorts were analyzed to validate the clinical relevance of the identified signaling pathways. The epigenetic and immunological impacts of lactate metabolism were assessed using glycolysis inhibitors (2-DG and oxamate) and genetic silencing of LDHA and LDHB.
Histone lactylation, specifically H3K18la, was significantly elevated in GC tissues and further elevated upon H. pylori infection. Pharmacological inhibition of glycolysis or LDHA/B double knockdown (DKD) markedly reduced H3K18la levels, suppressed GC cell proliferation, and restored CD8+ T cell-mediated cytotoxicity. Mechanistically, H3K18la directly bound to the HAS2 promoter, transcriptionally activating its expression. Upregulated HAS2 facilitated the nuclear translocation of c-MYC, which subsequently bound to the CD274 promoter to induce PD-L1 expression. Furthermore, c-MYC overexpression rescued PD-L1 levels and reversed the restored CD8+ T-cell cytotoxicity in LDHA/B-deficient GC cells. In vivo, the combination of oxamate and anti-PD-1 blockade synergistically enhanced CD8+ T-cell infiltration and exerted robust antitumor efficacy.
H. pylori-associated lactate-driven H3K18la promotes GC progression and immune evasion through the HAS2/c-MYC/PD-L1 axis. These findings provide preclinical support for combining metabolic inhibition with PD-1 blockade in GC, particularly in H. pylori-associated disease.
Authors
Chen Chen, Wang Wang, Wang Wang, Su Su, Shao Shao, Zhang Zhang, Wang Wang, Ge Ge, Zhou Zhou
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