CAF-secreted LOX promotes PD-L1 expression via histone Lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric Cancer

• Published in: Cellular signalling 2024-12, Vol.124, p.111462, Article 111462
• Main Authors: Li, Zedong, Liang, Panping, Chen, Zhengwen, Chen, Zehua, Jin, Tao, He, Fengjun, Chen, Xiaolong, Yang, Kun
• Format: Article
• Language: English
• Subjects: Animals; B7-H1 Antigen - metabolism; Cancer-associated fibroblasts; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; H3K18la; Histones - metabolism; Humans; Insulin-Like Growth Factor I - metabolism; Mice; Mice, Nude; PD-L1; Protein-Lysine 6-Oxidase - genetics; Protein-Lysine 6-Oxidase - metabolism; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Transforming Growth Factor beta - metabolism
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111462

In gastric cancer treatment, cancer-associated fibroblasts (CAF) may significantly influence the efficacy of immune checkpoint inhibitors by modulating PD-L1 expression. However, the precise mechanisms remain unclear. This study aims to explore the relationship between CAF and PD-L1 expression, providing new insights for improving PD-L1-targeted therapies. Using primary fibroblasts, transcriptome sequencing, ChIP-qPCR, and a lung metastasis model, we discovered that CAF secrete lysyl oxidase (LOX), which activates the TGFβ signaling pathway in gastric cancer cells, thereby promoting insulin-like growth factor 1(IGF1) expression. Upregulation of IGF1 enhances gastric cancer cell migration, epithelial-mesenchymal transition (EMT), and glycolysis. Additionally, we found that lactate accumulation leads to lysine 18 lactylation on histone H3 (H3K18la), which enriches at the PD-L1 promoter region, thus promoting PD-L1 transcription. These findings suggest that CAF may diminish the effectiveness of PD-1/PD-L1 blockade immunotherapy through LOX-induced glycolysis and lactate accumulation. Consequently, we have constructed a model of the interactions among CAF, lactate, and PD-L1 in gastric cancer progression, providing new experimental evidence for PD-L1-based immunotherapy. •CAF secrete Lysyl oxidase (LOX), which activates the TGFβ signaling pathway, leading to increased IGF1 expression and promoting cancer cell migration, EMT, and glycolysis.•Enhanced glycolysis results in lactate accumulation and lactylation of histone H3 at the PD-L1 promoter, inducing PD-L1 transcription.•A network model depicts interactions among CAF, lactate, and PD-L1 in gastric cancer, providing new insights for PD-1/PD-L1-based immunotherapy strategies.