DDR2/STAT3 正反馈环路通过上调 PD-L1 和募集 MDSCs 来调节奥沙利铂耐药 HCC 的免疫抑制微环境。

DDR2/STAT3 Positive Feedback Loop Mediates the Immunosuppressive Microenvironment by Upregulating PD-L1 and Recruiting MDSCs in Oxaliplatin-Resistant HCC.

机构信息

Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China; Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.

Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai, China.

出版信息

Cell Mol Gastroenterol Hepatol. 2024;18(4):101377. doi: 10.1016/j.jcmgh.2024.101377. Epub 2024 Jul 3.

DOI:10.1016/j.jcmgh.2024.101377

PMID:38969205

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11386308/

Abstract

BACKGROUND AND AIMS

Transcriptome sequencing revealed high expression of DDR2 in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC.

METHODS

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.

RESULTS

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, which was associated with PD-L1 upregulation and PMN-MDSCs accumulation. 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. Enzyme-linked immunosorbent 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.

CONCLUSIONS

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-MDSC recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.

摘要

背景与目的

转录组测序显示，DDR2 在奥沙利铂耐药肝癌（HCC）中高表达。本研究旨在探讨 DDR2 在 HCC 中奥沙利铂耐药和免疫逃逸中的作用。

方法

建立奥沙利铂耐药 HCC 细胞系。研究了 DDR2 与 STAT3 之间的相互作用，以及 DDR2/STAT3 介导的 PD-L1 上调和多形核髓系来源抑制细胞（PMN-MDSCs）在体外和体内积累的机制。

结果

发现 DDR2 诱导 STAT3 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 HCC 中发现了涉及 DDR2/STAT3 的正反馈回路，与 PD-L1 上调和 PMN-MDSCs 积累有关。DDR2 和 STAT3 的敲低使奥沙利铂耐药 HCC 细胞对奥沙利铂敏感，并导致肿瘤微环境中 PMN-MDSCs 减少和 CD8 T 细胞增加。酶联免疫吸附试验和 MDSC 迁移小室试验表明，奥沙利铂耐药 HCC 细胞通过 CCL20 招募 PMN-MDSCs。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，用 PD-L1 抗体联合 CCL20 阻断治疗对奥沙利铂耐药 HCC 具有显著的抗肿瘤作用。