Department of General Surgery, West China Hospital, Sichuan University, China; Gastric Cancer Center, West China Hospital, Sichuan University, China; Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, China; Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.
Department of General Surgery, West China Hospital, Sichuan University, China; Gastric Cancer Center, West China Hospital, Sichuan University, China; Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, China.
Cell Signal. 2024 Dec;124:111462. doi: 10.1016/j.cellsig.2024.111462. Epub 2024 Oct 10.
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.
在胃癌治疗中，癌症相关成纤维细胞（CAF）可能通过调节 PD-L1 的表达，显著影响免疫检查点抑制剂的疗效。然而，确切的机制尚不清楚。本研究旨在探讨 CAF 与 PD-L1 表达之间的关系，为改善 PD-L1 靶向治疗提供新的见解。我们使用原代成纤维细胞、转录组测序、ChIP-qPCR 和肺转移模型，发现 CAF 分泌赖氨酰氧化酶（LOX），该酶激活胃癌细胞中的 TGFβ 信号通路，从而促进胰岛素样生长因子 1（IGF1）的表达。IGF1 的上调增强了胃癌细胞的迁移、上皮间质转化（EMT）和糖酵解。此外，我们发现乳酸积累导致组蛋白 H3（H3K18la）赖氨酸 18 乳酰化，该修饰富集在 PD-L1 启动子区域，从而促进 PD-L1 转录。这些发现表明，CAF 可能通过 LOX 诱导的糖酵解和乳酸积累降低 PD-1/PD-L1 阻断免疫疗法的有效性。因此，我们构建了一个胃癌进展中 CAF、乳酸和 PD-L1 相互作用的模型，为基于 PD-L1 的免疫治疗提供了新的实验证据。
