1. Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8 + T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.
- Author
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Cai N, Cheng K, Ma Y, Liu S, Tao R, Li Y, Li D, Guo B, Jia W, Liang H, Zhao J, Xia L, Ding ZY, Chen J, and Zhang W
- Subjects
- Animals, Mice, Humans, Mutation, Programmed Cell Death 1 Receptor metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Tumor Escape genetics, Tumor Escape drug effects, Tumor Microenvironment immunology, Cell Line, Tumor, beta Catenin metabolism, beta Catenin genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular drug therapy, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Liver Neoplasms immunology, Liver Neoplasms drug therapy, Liver Neoplasms pathology, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase 9 genetics, CD8-Positive T-Lymphocytes immunology
- 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 CTNNB1GOF 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 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., Results: MMP9 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., Conclusions: CTNNB1GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1GOF HCC., Competing Interests: Competing interests: None declared., (© 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.)- Published
- 2024
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