N6-methyladenosine (m6A)-mediated messenger RNA signatures and the tumor immune microenvironment can predict the prognosis of hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it’s well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.

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Hydroxyl safflower yellow A regulates the tumor immune microenvironment to produce an anticancer effect in a mouse model of hepatocellular carcinoma

Oncology Letters ◽

10.3892/ol.2019.9946 ◽

2019 ◽

Cited By ~ 3

Author(s):

Yicong Ma ◽

Cuiling Feng ◽

Jingjing Wang ◽

Ziwei Chen ◽

Peng Wei ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Mouse Model ◽

Anticancer Effect ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

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CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma

FEBS Open Bio ◽

10.1002/2211-5463.12836 ◽

2020 ◽

Vol 10 (5) ◽

pp. 847-860 ◽

Cited By ~ 2

Author(s):

Chongren Ren ◽

Xiaojing Ren ◽

Dujuan Cao ◽

Haichao Zhao ◽

Zhensheng Zhai ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Cell Resistance ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

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Wnt/β-catenin Inhibitor ICG-001 Enhances the Antitumor Efficacy of Radiotherapy by Increasing Radiation-induced DNA Damage and Improving Tumor Immune Microenvironment in Hepatocellular Carcinoma

10.21203/rs.3.rs-57294/v1 ◽

2020 ◽

Author(s):

Yan Huang ◽

Hailong Sheng ◽

Yazhi Xiao ◽

Zhihong Zhang ◽

Yiyao Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Growth ◽

Signaling Pathway ◽

Critical Role ◽

Tumor Control ◽

Immune Microenvironment ◽

Tumor Bearing ◽

Pathway Activation ◽

Tumor Immune Microenvironment ◽

Radiotherapy Alone

Abstract Background: Radiotherapy has a promising anti-tumor effect in hepatocellular carcinoma (HCC), depending on the its regulatory effects on both cancer cells and tumor immune microenvironment (TME). Wnt/β-catenin signaling pathway activation, which is one of the most common alterations in HCC patients, has been reported to induce radioresistance, and also create immunosuppressive TME. However, it is unclear whether inhibition of wnt/β-catenin pathway could enhance the treatment efficacy of radiotherapy. In this study, we aim to explore the effect of wnt/β-catenin inhibitor ICG-001 in combination with radiotherapy and the underlying mechanism in HCC.Methods: C57BL/6 and nude mouse subcutaneous tumor models were used to evaluate the efficacy of different treatment regimens in tumor growth control, tumor recurrence inhibition and survival improvement. Flow cytometry was performed to assess the alterations of tumor infiltrating lymphocytes (TILs). Radioresistance was investigated by clone formation assay and γ-H2AX measurements. Wnt/β-catenin and cGAS/STING pathway activation was detected by immunoblotting. Results: The addition of ICG-001 to radiotherapy exhibited better anti-tumor control efficacy in tumor-bearing C57BL/6 mice than nude mice, which suggested that ICG-001 had a critical role in activating TME. The comprehensive analysis of TILs revealed that compared with radiotherapy alone, the combination of ICG-001 with radiotherapy boosted the infiltration and IFN-γ production ability of TIL CD8+ T cells, meanwhile reduced the number of TIL Tregs. Moreover, mechanism study demonstrated that ICG-001 exerted a radiosensitizing effect on HCC cells, thus leading to stronger activation of cGAS/STING signaling pathway upon radiotherapy in vitro and in vivo. Utilization of STING inhibitor, C-176, significantly impaired the synergetic effect of ICG-001 with radiotherapy on tumor control and TME activation. Furthermore, combination therapy led to a stronger immunologic memory and lasting anti-tumor immunity than radiotherapy, thus preventing tumor relapse in HCC tumor-bearing mice.Conclusion: Our findings showed that ICG-001 increased radioresistance and improved TME upon radiotherapy in HCC. Compared with radiotherapy alone, the combination of ICG-001 with radiotherapy displayed better therapeutic efficacy in inhibiting tumor growth, prolonging survival, and preventing recurrence in tumor-bearing mice. These data indicated that ICG-001 might be a potential synergetic treatment for radiotherapy and radioimmunotherapy in HCC.

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Reliability of a single-region sample to evaluate tumor immune microenvironment in hepatocellular carcinoma

Journal of Hepatology ◽

10.1016/j.jhep.2019.09.032 ◽

2020 ◽

Vol 72 (3) ◽

pp. 489-497 ◽

Cited By ~ 6

Author(s):

Ying-Chun Shen ◽

Chia-Lang Hsu ◽

Yung-Ming Jeng ◽

Ming-Chih Ho ◽

Cheng-Maw Ho ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Microenvironment ◽

Single Region ◽

Tumor Immune Microenvironment

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Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma

Genome Medicine ◽

10.1186/s13073-020-00796-5 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Hechen Huang ◽

Zhigang Ren ◽

Xingxing Gao ◽

Xiaoyi Hu ◽

Yuan Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Outcome ◽

Gut Microbiota ◽

Bile Acids ◽

Clinical Characteristics ◽

Tumor Burden ◽

Support Vector ◽

Immune Microenvironment ◽

Serum Bile Acids ◽

Tumor Immune Microenvironment

Abstract Background The gut-liver axis plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). However, the correlations between the gut microbiome and the liver tumor transcriptome in patients with HCC and the impact of the gut microbiota on clinical outcome are less well-understood. Methods Fecal samples collected from HBV-related HCC patients (n = 113) and healthy volunteers (n = 100) were subjected to 16S rRNA sequencing of the microbiome. After a rigorous selection process, 32 paired tumor and adjacent non-tumor liver tissues from the HCC group were subjected to next-generation sequencing (NGS) RNA-seq. The datasets were analyzed individually and integrated with clinical characteristics for combined analysis using bioinformatics approaches. We further verified the potential of the gut microbiota to predict clinical outcome by a random forest model and a support vector machine model. Results We found that Bacteroides, Lachnospiracea incertae sedis, and Clostridium XIVa were enriched in HCC patients with a high tumor burden. By integrating the microbiome and transcriptome, we identified 31 robust associations between the above three genera and well-characterized genes, indicating possible mechanistic relationships in tumor immune microenvironment. Clinical characteristics and database analysis suggested that serum bile acids may be important communication mediators between these three genera and the host transcriptome. Finally, among these three genera, six important microbial markers associated with tumor immune microenvironment or bile acid metabolism showed the potential to predict clinical outcome (AUC = 81%). Conclusions This study revealed that changes in tumor immune microenvironment caused by the gut microbiota via serum bile acids may be important factors associated with tumor burden and adverse clinical outcome. Gut microbes can be used as biomarkers of clinical features and outcomes, and the microbe-associated transcripts of host tumors can partly explain how gut microbiota promotes HCC pathogenesis.

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Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms22115801 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5801

Author(s):

Kyoko Oura ◽

Asahiro Morishita ◽

Joji Tani ◽

Tsutomu Masaki

Keyword(s):

Hepatocellular Carcinoma ◽

Immunosuppressive Therapy ◽

Cytotoxic T Lymphocyte ◽

Adoptive Cell Transfer ◽

Treatment Modalities ◽

Immune Microenvironment ◽

First Line Therapy ◽

Vegf Inhibitor ◽

Tumor Immune Microenvironment ◽

Immunological Classification

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.

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Potential lncRNA Biomarkers for HBV-Related Hepatocellular Carcinoma Diagnosis Revealed by Analysis on Coexpression Network

BioMed Research International ◽

10.1155/2021/9972011 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Shunqiang Nong ◽

Xiaohao Chen ◽

Zechen Wang ◽

Guidan Xu ◽

Wujun Wei ◽

...

Keyword(s):

Gene Expression ◽

Machine Learning ◽

Hepatocellular Carcinoma ◽

Functional Annotation ◽

Expression Profiles ◽

Functional Enrichment ◽

Coexpression Network ◽

Support Vector ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment

Background. Increasing evidence demonstrated that long noncoding RNA (lncRNA) could affect inflammatory tumor immune microenvironment by modulating gene expression and could be used as a biomarker for HBC-related hepatocellular carcinoma (HCC) but still needs further research. The aim of the present study was to determine an lncRNA signature for the diagnosis of HBV-related HCC. Methods. HBV-related HCC expression profiles (GSE55092, GSE19665, and GSE84402) were abstracted from the GEO (Gene Expression Omnibus) data resource, and R package limma and RobustRankAggreg were employed to identify common differentially expressed genes (DEGs). Using machine learning, optimal diagnostic lncRNA molecular markers for HBV-related HCC were identified. The expression of candidate lncRNAs was cross-validated in GSE121248, and an ROC (receiver operating characteristic) curve of lncRNA biomarkers was carried out. Additionally, a coexpression network and functional annotation was built, after which a PPI (protein-protein interaction) network along with module analysis were conducted with the Cytoscape open source software. Result. A total of 38 DElncRNAs and 543 DEmRNAs were identified with a fold change larger than 2.0 and a P value < 0.05. By machine learning, AL356056.2, AL445524.1, TRIM52-AS1, AC093642.1, EHMT2-AS1, AC003991.1, AC008040.1, LINC00844, and LINC01018 were screened out as optional diagnostic lncRNA biosignatures for HBV-related HCC. The AUC (areas under the curve) of the SVM (support vector machine) model and random forest model were 0.957 and 0.904, respectively, and the specificity and sensitivity were 95.7 and 100% and 94.3 and 86.5%, respectively. The results of functional enrichment analysis showed that the integrated coexpressed DEmRNAs shared common cascades in the p53 signaling pathway, retinol metabolism, PI3K-Akt signaling cascade, and chemical carcinogenesis. The integrated DEmRNA PPI network complex was found to be comprised of 87 nodes, and two vital modules with a high degree were selected with the MCODE app. Conclusion. The present study identified nine potential diagnostic biomarkers for HBV-related HCC, all of which could potentially modulated gene expression related to inflammatory conditions in the tumor immune microenvironment. The functional annotation of the target DEmRNAs yielded novel evidence in evaluating the precise functions of lncRNA in HBV-related HCC.

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