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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Vydáno v:	Gut Ročník 73; číslo 6; s. 985 - 999
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.06.2024 BMJ Publishing Group LTD BMJ Publishing Group
Edice:	Original research
Témata:	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 CANCER IMMUNOBIOLOGY MUTATIONS IMMUNOTHERAPY HEPATOCELLULAR CARCINOMA
ISSN:	0017-5749, 1468-3288, 1468-3288
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Shrnutí:	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.
Bibliografie:	Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 NC, KC, YM and SL are joint first authors.
ISSN:	0017-5749 1468-3288 1468-3288
DOI:	10.1136/gutjnl-2023-331342