Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Experimental hematology & oncology - 13(2024), 1 vom: 22. Feb., Seite 20 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shen, Xiao-Tian [VerfasserIn] |
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| Links: |
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| Themen: |
Collagen type I (Col1) |
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| Anmerkungen: |
Date Revised 24.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1186/s40164-024-00476-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368784517 |
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| 245 | 1 | 0 | |a Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma |
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| 500 | |a Date Revised 24.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Collagen type I (Col1) | |
| 650 | 4 | |a Extracellular matrix (ECM) | |
| 650 | 4 | |a Hepatocellular carcinoma (HCC) | |
| 650 | 4 | |a Immune checkpoint inhibitor (ICI) | |
| 650 | 4 | |a Neutrophil extracellular traps (NETs) | |
| 700 | 1 | |a Xie, Sun-Zhe |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Tian-Tian |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Bei-Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yun-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xu-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Shun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Le |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Kang-Kang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Wen-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ju-Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jin-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Qiong-Zhu |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lu-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Lun-Xiu |e verfasserin |4 aut | |
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