转录组测序显示盘状蛋白结构域受体 2 (DDR2) 在奥沙利铂耐药性肝细胞癌 (HCC) 中高表达。本研究旨在探讨DDR2在HCC奥沙利铂耐药和免疫逃避中的作用。建立奥沙利铂耐药HCC细胞系。研究了 DDR2 和 STAT3 之间的相互作用，以及体外和体内 DDR2/STAT3 介导的 PD-L1 上调和多形核骨髓源性抑制细胞 (PMN-MDSC) 积累所涉及的机制。 STAT3 的磷酸化，导致其核转位。相反，STAT3 的激活增强了 DDR2 的表达。在奥沙利铂耐药性 HCC 中发现了涉及 DDR2/STAT3 的正反馈回路，与 PD-L1 上调相关，并且在奥沙利铂耐药性 HCC 中发现了 PMN-MDSC 积累。 DDR2和STAT3的敲低使奥沙利铂耐药的HCC细胞对奥沙利铂敏感，并导致肿瘤微环境中PMN-MDSC减少和CD8 T细胞增加。 ELISA阵列和MDSC跨孔迁移测定表明，奥沙利铂耐药的HCC细胞通过CCL20招募PMN-MDSC。双荧光素酶报告基因检测表明 STAT3 可以直接增强 PD-L1 和 CCL20 的转录。此外，PD-L1 抗体联合 CCL20 阻断治疗对奥沙利铂耐药性 HCC 具有显着的抗肿瘤作用。我们的研究结果揭示了涉及 DDR2 和 STAT3 的正反馈机制，介导免疫抑制微环境并通过 PD-促进奥沙利铂耐药和免疫逃避。 L1 上调和 PMN-MDSC 募集。靶向 DDR2/STAT3 通路可能是克服 HCC 免疫逃逸和化疗耐药性的一种有前途的治疗策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Transcriptome sequencing revealed high expression of discoidin domain receptor 2 (DDR2) in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC.Oxaliplatin-resistant HCC cell lines were established. The interaction between DDR2 and STAT3 was investigated, along with the mechanisms involved in DDR2/STAT3-mediated PD-L1 upregulation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) accumulation both in vitro and in vivo.DDR2 was found to induce the phosphorylation of STAT3, leading to its nuclear translocation. Conversely, the activation of STAT3 enhanced DDR2 expression. A positive feedback loop involving DDR2/STAT3 was identified in oxaliplatin-resistant HCC, associated with PD-L1 upregulation and PMN-MDSCs accumulation was identified in oxaliplatin-resistant HCC. Knockdown of DDR2 and STAT3 sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in decreased PMN-MDSCs and increased CD8+ T cells in the tumor microenvironment. ELISA array and MDSC transwell migration assays indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through CCL20. Dual luciferase reporter assays demonstrated that STAT3 can directly enhance the transcription of PD-L1 and CCL20. Furthermore, treatment with a PD-L1 antibody in combination with CCL20 blockade had significant antitumor effects on oxaliplatin-resistant HCC.Our findings revealed a positive feedback mechanism involving DDR2 and STAT3 that mediates the immunosuppressive microenvironment and promotes oxaliplatin resistance and immune evasion via PD-L1 upregulation and PMN-MDSCs recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.