Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer.

Abstract

The epigenetic regulatory chemical lactate is a product of glycolysis. It can regulate gene expression through histone lactylation, thereby promoting tumor proliferation, metastasis, and immunosuppression. In this study, a lactylation-related model for gastric cancer (GC) was constructed, and its relationships to prognosis, immune cell infiltration, and immunotherapy were investigated. By contrasting normal tissues and tumor tissues, four lactylation-related pathways that were substantially expressed in GC tissues were found in the GSEA database. Six lactylation-related genes were screened for bioinformatic analysis. The GC data sets from the TCGA and GEO databases were downloaded and integrated to perform cluster analysis, and the lactylation related model was constructed by secondary clustering. The fingding demonstrated that the lactylation score has a strong correlation with the overall survival rate from GC and the progression of GC. Mechanistic experiments showed that abundant immune cell infiltration (macrophages showed the highest degree of infiltration) and increased genetic instability are traits of high lactylation scores. Immune checkpoint inhibitors (ICIs) demonstrated a reduced response rate in GC with high lactylation scores. At the same time, tumors with high lactylation scores had high Tumor Immune Dysfunction and Exclusion scores, which means that they had a higher risk of immune evasion and dysfunction. These findings indicate that the lactylation score can be used to predict the malignant progression and immune evasion of GC. This model also can guide the treatment response to ICIs of GC. The constructed model of the lactate gene is also expected to become a potential therapeutic target for GC and diagnostic marker.