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Feasibility of hepatocellular carcinoma treatment based on the tumor microenvironment.

ABSTRACT: The incidence of liver cancer is extremely high worldwide and poses a serious threat to human life and health. But at present, apart from radiotherapy, chemotherapy, liver transplantation, and early resection, sorafenib was the main systemic therapy proven to have clinical efficacy for unresectable liver cancer (HCC) until 2017. Despite the emerging immunotherapy in the past decade with immune inhibitors such as PD - 1 being approved and applied to clinical treatment, there are still some patients with no response. This review aims to elucidate the mechanisms underlying the tumor microenvironment of hepatocellular carcinoma and thus analyze the effectiveness of targeting the tumor microenvironment to improve the therapeutic efficacy of hepatocellular carcinoma, including the effectiveness and feasibility of immunotherapy, tumor oncolytic viruses and anti-vascular proliferation therapy.

SUBMITTER: Wang H

PROVIDER: S-EPMC9513472 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Feasibility of hepatocellular carcinoma treatment based on the tumor microenvironment.

Wang Haiqiang H Shi Fan F Zheng Shudan S Zhao Mei M Pan Zimeng Z Xiong Li L Zheng Lihong L

Frontiers in oncology 20220913

The incidence of liver cancer is extremely high worldwide and poses a serious threat to human life and health. But at present, apart from radiotherapy, chemotherapy, liver transplantation, and early resection, sorafenib was the main systemic therapy proven to have clinical efficacy for unresectable liver cancer (HCC) until 2017. Despite the emerging immunotherapy in the past decade with immune inhibitors such as PD - 1 being approved and applied to clinical treatment, there are still some patien ...[more]

PMID: 36176401

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Project description:Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.

Project description:IntroductionTumor purity takes on critical significance to the progression of solid tumors. The aim of this study was at exploring potential prognostic genes correlated with tumor purity in hepatocellular carcinoma (HCC) by bioinformatics analysis.MethodsThe ESTIMATE algorithm was applied for determining the tumor purity of HCC samples from The Cancer Genome Atlas (TCGA). The tumor purity-associated genes with differential expression (DEGs) were identified based on overlap analysis, weighted gene co-expression network analysis (WGCNA), and differential expression analysis. The prognostic genes were identified in terms of the prognostic model construction based on the Kaplan-Meier (K-M) survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses. The expression of the above-described genes was further validated by the GSE105130 dataset from the Gene Expression Omnibus (GEO) database. We also characterized the clinical and immunophenotypes of prognostic genes. Gene set enrichment analysis (GSEA) was carried out for exploring the biological signaling pathway.ResultsA total of 26 tumor purity-associated DEGs were identified, which were involved in biological processes such as immune/inflammatory responses and fatty acid elongation. Ultimately, we identified ADCK3, HK3, and PPT1 as the prognostic genes for HCC. Moreover, HCC patients exhibiting higher ADCK3 expression and lower HK3 and PPT1 expressions had a better prognosis. Furthermore, high HK3 and PPT1 expressions and low ADCK3 expression resulted in high tumor purity, high immune score, high stromal score, and high ESTIMATE score. GSEA showed that the abovementioned prognostic genes showed a significant correlation with immune-inflammatory response, tumor growth, and fatty acid production/degradation.DiscussionIn conclusion, this study identified novel predictive biomarkers (ADCK3, HK3, and PPT1) and studied the underlying molecular mechanisms of HCC pathology initially.

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Feasibility of hepatocellular carcinoma treatment based on the tumor microenvironment.

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Feasibility of hepatocellular carcinoma treatment based on the tumor microenvironment.

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