scholarly journals 996P Characterization of the tumor immune microenvironment in hepatocellular carcinoma: Prognostic value of M0-macrophage high subtype

2020 ◽  
Vol 31 ◽  
pp. S694
Author(s):  
M. Farha ◽  
N.K. Jairath ◽  
I. El Naqa ◽  
T. Lawrence
Keyword(s):  
Hepatocellular Carcinoma ◽  
Prognostic Value ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals Identification of Prognostic Glycolysis-Related lncRNA Signature in Tumor Immune Microenvironment of Hepatocellular Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Yang Bai ◽  
Haiping Lin ◽  
Jiaqi Chen ◽  
Yulian Wu ◽  
Shi’an Yu
Keyword(s):  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Risk Score ◽  
Prognostic Value ◽  
Enrichment Analysis ◽  
Immune Microenvironment ◽  
Prognostic Accuracy ◽  
Tumor Immune Microenvironment ◽  
Cox Analysis

Purpose: The purpose of this study was to construct a novel risk scoring model with prognostic value that could elucidate tumor immune microenvironment of hepatocellular carcinoma (HCC).Samples and methods: Data were obtained through The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were carried out to screen for glycolysis-related long noncoding RNAs (lncRNAs) that could provide prognostic value. Finally, we established a risk score model to describe the characteristics of the model and verify its prediction accuracy. The receiver operating characteristic (ROC) curves of 1, 3, and 5 years of overall survival (OS) were depicted with risk score and some clinical features. ESTIMATE algorithm, single-sample gene set enrichment analysis (ssGSEA), and CIBERSORT analysis were employed to reveal the characteristics of tumor immune microenvironment in HCC. The nomogram was drawn by screening indicators with high prognostic accuracy. The correlation of risk signature with immune infiltration and immune checkpoint blockade (ICB) therapy was analyzed. After enrichment of related genes, active behaviors and pathways in high-risk groups were identified and lncRNAs related to poor prognosis were validated in vitro. Finally, the impact of MIR4435-2HG upon ICB treatment was uncovered.Results: After screening through multiple steps, four glycolysis-related lncRNAs were obtained. The risk score constructed with the four lncRNAs was found to significantly correlate with prognosis of samples. From the ROC curve of samples with 1, 3, and 5 years of OS, two indicators were identified with high prognostic accuracy and were used to draw a nomogram. Besides, the risk score significantly correlated with immune score, immune-related signature, infiltrating immune cells (i.e. B cells, etc.), and ICB key molecules (i.e. CTLA4,etc.). Gene enrichment analysis indicated that multiple biological behaviors and pathways were active in the high-risk group. In vitro validation results showed that MIR4435-2HG was highly expressed in the two cell lines, which had a significant impact on the OS of samples. Finally, we corroborated that MIR4435-2HG had intimate relationship with ICB therapy in hepatocellular carcinoma.Conclusion: We elucidated the crucial role of risk signature in immune cell infiltration and immunotherapy, which might contribute to clinical strategies and clinical outcome prediction of HCC.

scholarly journals Characterization of the Tumor Immune Microenvironment Identifies M0 Macrophage-Enriched Cluster as a Poor Prognostic Factor in Hepatocellular Carcinoma

2020 ◽  
pp. 1002-1013
Author(s):  
Mark Farha ◽  
Neil K. Jairath ◽  
Theodore S. Lawrence ◽  
Issam El Naqa
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Prognostic Value ◽  
Immune Cell ◽  
Multivariable Analysis ◽  
Immune Microenvironment ◽  
Poor Prognostic Factor ◽  
Kaplan Meier ◽  
Programmed Death ◽  
Tumor Immune Microenvironment

PURPOSE Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and a high recurrence rate. The tumor immune microenvironment in HCC has been characterized as shifted toward immunosuppression. We conducted a genomic data-driven classification of immune microenvironment HCC subtypes. In addition, we demonstrated their prognostic value and suggested a potential therapeutic targeting strategy. METHODS RNA sequencing data from The Cancer Genome Atlas–Liver Hepatocellular Carcinoma was used (n = 366). Abundance of immune cells was imputed using CIBERSORT and visualized using unsupervised hierarchic clustering. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox regression. Differential expression and gene set enrichment analyses were conducted on immune clusters with poor OS and high programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) coexpression. A scoring metric combining differentially expressed genes and immune cell content was created, and its prognostic value and immune checkpoint blockade response prediction was evaluated. RESULTS Two clusters were characterized by macrophage enrichment, with distinct M0Hi and M2Hi subtypes. M2Hi ( P = .038) and M0Hi ( P = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0Hi and M2Hi treated with sorafenib had decreased OS ( P = .041), and angiogenesis hallmark genes were enriched in the M0Hi group. CXCL6 and POSTN were overexpressed in both the M0Hi and the PD-1Hi/PD-L1Hi groups. A score consisting of CXCL6 and POSTN expression and absolute M0 macrophage content was discriminatory for OS (intermediate: hazard ratio [HR], 1.59; P ≤ .001; unfavorable: HR, 2.08; P = .04). CONCLUSION Distinct immune cell clusters with macrophage predominance characterize an aggressive HCC phenotype, defined molecularly by angiogenic gene enrichment and clinically by poor prognosis and sorafenib response. This novel immunogenomic signature may aid in stratification of unresectable patients to receive checkpoint inhibitor and antiangiogenic therapy combinations.

scholarly journals pH regulators to target the tumor immune microenvironment in human hepatocellular carcinoma

2018 ◽  
Vol 7 (7) ◽  
pp. e1445452 ◽  
Author(s):  
Olga Kuchuk ◽  
Alessandra Tuccitto ◽  
Davide Citterio ◽  
Veronica Huber ◽  
Chiara Camisaschi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Human Hepatocellular Carcinoma ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Yaojie Fu ◽  
Shanshan Liu ◽  
Shan Zeng ◽  
Hong Shen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Cell Lung ◽  
Immune Microenvironment ◽  
Liver Malignancy ◽  
The Third ◽  
Clinical Investigations ◽  
Tumor Immune Microenvironment ◽  
Novel Strategy ◽  
Immunosuppressive Microenvironment ◽  
Related Mortality

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.

scholarly journals 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

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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