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

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2024-10-10 DOI:10.1016/j.cellsig.2024.111462

Zedong Li , Panping Liang , Zhengwen Chen , Zehua Chen , Tao Jin , Fengjun He , Xiaolong Chen , Kun Yang

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引用次数: 0

Abstract

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.

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CAF 分泌的 LOX 通过组蛋白乳酸化促进 PD-L1 的表达，并通过 TGFβ/IGF1 信号调节胃癌中肿瘤的 EMT

在胃癌治疗中，癌相关成纤维细胞（CAF）可能会通过调节 PD-L1 的表达而显著影响免疫检查点抑制剂的疗效。然而，其确切机制仍不清楚。利用原代成纤维细胞、转录组测序、ChIP-qPCR和肺转移模型，我们发现CAF能分泌赖氨酰氧化酶（LOX），它能激活胃癌细胞的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，我们还发现乳酸盐的积累会导致组蛋白 H3 上的赖氨酸 18 乳化（H3K18la），这种乳化富集在 PD-L1 启动子区域，从而促进 PD-L1 的转录。这些研究结果表明，CAF可能会通过LOX诱导的糖酵解和乳酸积累削弱PD-1/PD-L1阻断免疫疗法的效果。因此，我们构建了CAF、乳酸和PD-L1在胃癌进展中的相互作用模型，为基于PD-L1的免疫疗法提供了新的实验证据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.