Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy
ObjectiveThe gain of function (GOF) CTNNB1 mutations (CTNNB1GOF) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-...
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| Veröffentlicht in: | Gut Jg. 73; H. 6; S. 985 - 999 |
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| Hauptverfasser: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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England
BMJ Publishing Group Ltd and British Society of Gastroenterology
01.06.2024
BMJ Publishing Group LTD BMJ Publishing Group |
| Schriftenreihe: | Original research |
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| ISSN: | 0017-5749, 1468-3288, 1468-3288 |
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| Abstract | ObjectiveThe gain of function (GOF) CTNNB1 mutations (CTNNB1GOF) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.DesignRNA sequencing was performed to identify the key downstream genes of CTNNB1GOF 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.ResultsMMP9 was significantly upregulated in CTNNB1GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-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.ConclusionsCTNNB1GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1GOF HCC. |
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| AbstractList | 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.OBJECTIVEThe 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.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.DESIGNRNA 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.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 β-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.RESULTSMMP9 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 β-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.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.CONCLUSIONSCTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC. ObjectiveThe gain of function (GOF) CTNNB1 mutations (CTNNB1GOF) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.DesignRNA sequencing was performed to identify the key downstream genes of CTNNB1GOF 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.ResultsMMP9 was significantly upregulated in CTNNB1GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-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.ConclusionsCTNNB1GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1GOF HCC. The gain of function (GOF) CTNNB1 mutations (CTNNB1 ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC. RNA sequencing was performed to identify the key downstream genes of CTNNB1 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. MMP9 was significantly upregulated in CTNNB1 HCC. MMP9 suppressed infiltration and cytotoxicity of CD8 T cells, which was critical for CTNNB1 to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 downregulated sirtuin 2 (SIRT2), resulting in promotion of β-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. CTNNB1 induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 HCC. |
| Author | Ma, Yue Li, Danfeng Guo, Bin Liang, Huifang Xia, Limin Zhao, Jianping Liu, Sha Zhang, Wanguang Tao, Ran Chen, Jinhong Ding, Ze-yang Cai, Ning Jia, Wenlong Li, Yani Cheng, Kun |
| AuthorAffiliation | 1 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 2 Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University , Shanghai , People's Republic of China 3 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 |
| AuthorAffiliation_xml | – name: 3 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 – name: 2 Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University , Shanghai , People's Republic of China – name: 1 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 |
| Author_xml | – sequence: 1 givenname: Ning orcidid: 0009-0003-0527-9768 surname: Cai fullname: Cai, Ning organization: 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 – sequence: 2 givenname: Kun surname: Cheng fullname: Cheng, Kun organization: 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 – sequence: 3 givenname: Yue surname: Ma fullname: Ma, Yue organization: Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, People's Republic of China – sequence: 4 givenname: Sha surname: Liu fullname: Liu, Sha organization: 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 – sequence: 5 givenname: Ran surname: Tao fullname: Tao, Ran organization: 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 – sequence: 6 givenname: Yani surname: Li fullname: Li, Yani organization: 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 – sequence: 7 givenname: Danfeng surname: Li fullname: Li, Danfeng organization: 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 – sequence: 8 givenname: Bin surname: Guo fullname: Guo, Bin organization: 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 – sequence: 9 givenname: Wenlong surname: Jia fullname: Jia, Wenlong organization: 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 – sequence: 10 givenname: Huifang surname: Liang fullname: Liang, Huifang organization: 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 – sequence: 11 givenname: Jianping surname: Zhao fullname: Zhao, Jianping organization: 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 – sequence: 12 givenname: Limin orcidid: 0000-0002-6327-6034 surname: Xia fullname: Xia, Limin organization: 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 – sequence: 13 givenname: Ze-yang surname: Ding fullname: Ding, Ze-yang email: zyding@tjh.tjmu.edu.cn organization: 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 – sequence: 14 givenname: Jinhong orcidid: 0000-0003-0952-9990 surname: Chen fullname: Chen, Jinhong email: jinhongch@hotmail.com organization: Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, People's Republic of China – sequence: 15 givenname: Wanguang surname: Zhang fullname: Zhang, Wanguang email: wgzhang@tjh.tjmu.edu.cn organization: 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 |
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| DOI | 10.1136/gutjnl-2023-331342 |
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| Issue | 6 |
| Keywords | CANCER IMMUNOBIOLOGY MUTATIONS IMMUNOTHERAPY HEPATOCELLULAR CARCINOMA |
| Language | English |
| License | This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
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| Snippet | ObjectiveThe gain of function (GOF) CTNNB1 mutations (CTNNB1GOF) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1.... The gain of function (GOF) CTNNB1 mutations (CTNNB1 ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we... The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here,... |
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| SubjectTerms | Animal models Animals beta Catenin - genetics beta Catenin - metabolism CANCER IMMUNOBIOLOGY Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - immunology Carcinoma, Hepatocellular - pathology CD8 antigen CD8-Positive T-Lymphocytes - immunology Cell Line, Tumor Cell-mediated immunity Chemokine receptors Chemokines Consortia CXCR3 protein Cytotoxicity Datasets Dendritic cells Down-regulation Flow cytometry G protein-coupled receptors Gelatinase B Gene flow Genes Genomes HEPATOCELLULAR CARCINOMA Hepatology Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immune evasion IMMUNOTHERAPY Intracellular signalling Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - genetics Liver Neoplasms - immunology Liver Neoplasms - pathology Lymphocytes Lymphocytes T Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Medical prognosis Metalloproteinase Metastases Mice Microenvironments Mutation MUTATIONS PD-1 protein Phosphoprotein phosphatase Plasmids Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed Cell Death 1 Receptor - metabolism Protein phosphatase Proteins Proteomics Transcription activation Tumor Escape - drug effects Tumor Escape - genetics Tumor Microenvironment - immunology Tumors β-Catenin |
| Title | Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy |
| URI | https://gut.bmj.com/content/early/2023/12/12/gutjnl-2023-331342.full https://www.ncbi.nlm.nih.gov/pubmed/38123979 https://www.proquest.com/docview/3053010471 https://www.proquest.com/docview/2904575201 https://pubmed.ncbi.nlm.nih.gov/PMC11103337 |
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