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Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma

Authors :
Xiao-Tian Shen
Sun-Zhe Xie
Xin Zheng
Tian-Tian Zou
Bei-Yuan Hu
Jing Xu
Lu Liu
Yun-Feng Xu
Xu-Feng Wang
Hao Wang
Shun Wang
Le Zhu
Kang-Kang Yu
Wen-Wei Zhu
Lu Lu
Ju-Bo Zhang
Jin-Hong Chen
Qiong-Zhu Dong
Lu-Yu Yang
Lun-Xiu Qin
Source :
Experimental Hematology & Oncology, Vol 13, Iss 1, Pp 1-18 (2024)
Publication Year :
2024
Publisher :
BMC, 2024.

Abstract

Abstract Background 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. Methods 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. Results 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. Conclusions 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.

Details

Language :
English
ISSN :
21623619
Volume :
13
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Experimental Hematology & Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.11f20552fc3944ccb8a7f193cd109f08
Document Type :
article
Full Text :
https://doi.org/10.1186/s40164-024-00476-9