MTDH antisense oligonucleotides reshape the immunosuppressive tumor microenvironment to sensitize Hepatocellular Carcinoma to immune checkpoint blockade therapy. (10th August 2022)

• Record Type: Journal Article
• Authors: Wan, Jing-Lei; Wang, Biao; Wu, Mei-Lan; Li, Jie; Gong, Ruo-Mu; Song, Li-Na; Zhang, Han-Shuo; Zhu, Gui-Qi; Chen, Shi-Ping; Cai, Jia-Liang; Xing, Xiao-Xia; Wang, Ya-Dong; Yang, Yi; Cai, Cheng-Zhe; Huang, Run; Liu, Hua; Dai, Zhi
• Is Part Of: Cancer letters. Volume 541(2022)
• Publication Date: 2022-08-10
• Subjects: Immunotherapy -- Immune infiltration -- ASO -- PD-L1 -- HCC; ASO antisense oligonucleotide -- BLI bioluminescence imaging -- Cas9 CRISPR-associated protein 9 -- CRISPR clustered regularly interspaced short palindromic repeats -- HCC hepatocellular carcinoma -- ICB immune checkpoint blockade -- IF immunofluorescence -- IFN-γ interferon-γ -- IHC immunohistochemistry -- LHD lung-homing domain -- LIHC liver hepatocellular carcinoma -- mAb monoclonal antibody -- NLS nuclear localization signal -- OS overall survival -- PD progressive disease -- PD-1 programmed cell death 1 -- PD-L1 programmed cell death ligand 1 -- PFS progression-free survival -- ROC receiver operating characteristic -- sgRNA small guide RNA -- shRNA short hairpin RNA -- siRNA small interfering RNA -- ssGSEA single sample gene set enrichment analysis -- TCGA the cancer genome atlas -- TMD transmembrane domain; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.215750
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Immune checkpoint blockade (ICB) therapy is an important treatment option for individuals with cancer, but it has certain limitations. Identifying a better target that can overcome tumor immune escape and stimulate T cell activity is critical. This research aimed to delve into the molecular mechanism underlying the immunoregulatory function of metadherin (MTDH), which is a novel and potential therapeutic target in hepatocellular cancer (HCC). A small interfering RNA library was screened using the luciferase reporter assay and PD-L1 promoter. The Cancer Genome Atlas database and HCC tissues were used to investigate the relationship between MTDH and PD-L1. The association between MTDH and β-catenin/lymphoid enhancer binding factor (LEF-1) was discovered by co-immunoprecipitation. The chromatin immunoprecipitation assay was used to investigate the interaction of MTDH with the PD-L1 promoter when LEF-1 expression was silenced. Locked nucleic acid antisense oligonucleotides (ASOs) were used to inhibit MTDH. We utilized in vitro co-cultures and in vivo syngeneic tumor development experiments to confirm the effectiveness of MTDH ASO combined with PD-1 monoclonal antibody (mAb). MTDH was demonstrated to be a PD-L1 modulator. MTDH increased PD-L1 expression and upregulated PD-L1 transcriptional activity through β-catenin/LEF-1 signaling. More importantly, MTDH ASO improved the anti-PD-1 response and increased cytotoxic T-cell infiltration in PD-1 mAb-treated malignancies. MTDH effectively predicts the therapeutic efficacy of ICB therapy. Our results imply that combining MTDH ASO with PD-1 mAb could be a promising therapeutic strategy for HCC. In addition, MTDH is a potential novel biomarker for predicting the effectiveness of immune checkpoint inhibitor treatment. Highlights: Identify MTDH as a potential PD-L1 modulator in HCC. CD8 + T cells were negatively correlated with MTDH in HCC. Pharmacologic inhibition of MTDH led to intense infiltration of CD8 + T cells and sensitized tumors to anti-PD-1 therapy. MTDH may be used to assess anti-PD-1 therapy efficacy. Combination of MTDH ASO and anti-PD-1 provides therapeutic benefit.