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Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.
Cai, Ning; Cheng, Kun; Ma, Yue; Liu, Sha; Tao, Ran; Li, Yani; Li, Danfeng; Guo, Bin; Jia, Wenlong; Liang, Huifang; Zhao, Jianping; Xia, Limin; Ding, Ze-Yang; Chen, Jinhong; Zhang, Wanguang.
Afiliación
  • Cai N; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Cheng K; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Ma Y; Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, People's Republic of China.
  • Liu S; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Tao R; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Li Y; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Li D; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Guo B; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Jia W; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Liang H; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Zhao J; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Xia L; Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
  • Ding ZY; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China wgzhang@tjh.
  • Chen J; Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, People's Republic of China wgzhang@tjh.tjmu.edu.cn jinhongch@hotmail.com zyding@tjh.tjmu.edu.cn.
  • Zhang W; Hepatic Surgery Center, Clinical Medicine Research Center of Hepatic Surgery of Hubei Province, and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China wgzhang@tjh.
Gut ; 73(6): 985-999, 2024 May 10.
Article en En | MEDLINE | ID: mdl-38123979
ABSTRACT

OBJECTIVE:

The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.

DESIGN:

RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9.

RESULTS:

MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of ß-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC.

CONCLUSIONS:

CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Linfocitos T CD8-positivos / Metaloproteinasa 9 de la Matriz / Beta Catenina / Neoplasias Hepáticas Idioma: En Revista: Gut Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Linfocitos T CD8-positivos / Metaloproteinasa 9 de la Matriz / Beta Catenina / Neoplasias Hepáticas Idioma: En Revista: Gut Año: 2024 Tipo del documento: Article