Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM’s effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. We defined “a pro-tumor cirrhotic-ECM” which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors’ institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

中文翻译：

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肝硬化细胞外基质通过启动肝细胞癌中免疫抑制性中性粒细胞胞外陷阱的形成来减弱 aPD-1 治疗反应

肝细胞癌（HCC）与慢性肝病密切相关，特别是肝硬化，其细胞外基质（ECM）成分发生改变。肝硬化ECM对HCC免疫检查点抑制剂（ICI）反应的影响及其机制尚不清楚。在计算机模拟中，肝硬化 ECM 改变的蛋白质组学和病理学评估应用于临床队列。使用 ECM 操作的多个临床前模型来评估肝硬化 ECM 对 ICI 治疗的影响。在计算机模拟中，应用流式细胞术和 IHC 来探索肝硬化 ECM 如何影响 HCC 微环境。进行体外和体内实验以确定肝硬化 ECM 如何破坏 ICI 治疗的机制。我们将其定义为“促肿瘤肝硬化 ECM”，其特点是 1 型胶原蛋白 (Col1) 上调。肝硬化-ECM/Col1 与 TCGA 泛癌队列和作者所在机构以及多个临床前模型中 HCC 患者的 T 细胞功能受损和有限的抗 PD-1 (aPD-1) 反应密切相关。从机械角度来看，肝硬化-ECM/Col1通过触发Col1-DDR1-NFκB-CXCL8轴精心策划了免疫抑制微环境（TME），该轴启动中性粒细胞胞外陷阱（NET）形成，以保护HCC细胞免于攻击T细胞并阻止T细胞接近。Nilotinib 是一种 DDR1 抑制剂，可逆转中性粒细胞/NETs 主导的 TME，并有效增强 HCC 对 aPD-1 的反应。肝硬化 ECM 调节了 HCC 中 NET 富集的 TME，产生了免疫抑制性 TME，并削弱了 ICI 效率。Col1 受体 DDR1 可能是与 ICI 协同使用以克服 ECM 介导的 ICI 耐药性的潜在靶点。这些为克服 HCC 的 ICI 耐药性提供了机械见解和新颖的策略。