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

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

doi:10.1186/s40164-024-00476-9

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

Exp Hematol Oncol. 2024 Feb 22;13(1):20. doi: 10.1186/s40164-024-00476-9.

Authors

Xiao-Tian Shen^#^{1

2}, Sun-Zhe Xie^#^{1

2}, Xin Zheng^#^{1

2}, Tian-Tian Zou^{1

2}, Bei-Yuan Hu², Jing Xu³, Lu Liu⁴, Yun-Feng Xu^{1

2}, Xu-Feng Wang^{1

2}, Hao Wang^{1

2}, Shun Wang^{1

2}, Le Zhu^{1

2}, Kang-Kang Yu⁴, Wen-Wei Zhu^{1

2}, Lu Lu^{1

2}, Ju-Bo Zhang⁴, Jin-Hong Chen^{1

2}, Qiong-Zhu Dong^{1

2}, Lu-Yu Yang^{5

6}, Lun-Xiu Qin^{7

8}

Affiliations

¹ Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
² Cancer Metastasis Institute, Fudan University, Shanghai, China.
³ Department of Dermatology, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
⁴ Department of Infection Disease, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
⁵ Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China. yangluyu@huashan.org.cn.
⁶ Cancer Metastasis Institute, Fudan University, Shanghai, China. yangluyu@huashan.org.cn.
⁷ Department of General Surgery, Huashan Hospital, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China. qinlx@fudan.edu.cn.
⁸ Cancer Metastasis Institute, Fudan University, Shanghai, China. qinlx@fudan.edu.cn.

^# Contributed equally.

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.

Keywords: Collagen type I (Col1); Extracellular matrix (ECM); Hepatocellular carcinoma (HCC); Immune checkpoint inhibitor (ICI); Neutrophil extracellular traps (NETs).

Abstract

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