Tricking an ancient immune function to eradicate hepatocellular carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Miyazaki T
PROVIDER: S-EPMC4905303 | biostudies-other | 2015 Jul-Sep
REPOSITORIES: biostudies-other
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Project description:Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
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Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, and advanced HCC generally caries a poor prognosis. The treatment of advanced disease is limited to sorafenib, which provides only a limited improvement in survival, and novel therapies are, thus, sorely needed. Among emerging alternative approaches, immune checkpoint inhibitors are a particularly promising treatment modality. In this review, we summarize current knowledge of the mechanisms for the two primary targets of immune checkpoint inhibitors and discuss the relevance of these pathways to the immunology of HCC. We also review the state of ongoing and forthcoming trials of immune checkpoint blockade in HCC.
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Project description:The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further.
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Project description:Objective The hepatitis B virus (HBV) infection led to hepatitis, which was one of common reasons for hepatocellular carcinoma (HCC). The immune microenvironment alteration played a crucial role in this process. The study aimed to identify immune-related long noncoding RNAs (lncRNAs) in HBV-related HCC and explore potential mechanisms. Methods In total, 1,072 immune‐related genes (IRGs) were enriched in different co-expression modules with weighted gene co-expression network analysis (WGCNA) combining the corresponding clinical features in HBV-related HCC. The immune-related lncRNAs were selected from the crucial co-expression model based on the correlation analysis with IRGs. The immune-related lncRNAs were furtherly used to construct prognostic signature by the Cox proportional hazards regression and Lasso regression. Furthermore, the proliferation and migration ability of lncRNA SNHG10 were verified in vitro. Results A total of nine co-expression modules were identified by WGCNA of which the “red” co-expression module was most correlated with various clinical characteristics. Additionally, the IRGs in this module were significantly enriched in multiple immune-related pathways. The twelve immune-related lncRNAs prognostic signature (HAND2-AS1, LINC00844, SNHG10, MALAT1, LINC00460, LBX2-AS1, MIR31HG, SEMA6A-AS1, LINC1278, LINC00514, CTBP-AS2, and LINC00205) was constructed. The risk score was an independent risk factor in HBV-related HCC and verified by principal components analysis (PCA), nomogram, and PCR between different cell lines. Moreover, the proportion of immune cells were significantly different between high-risk score group and low-risk score group. The malignant behavior of Hep3B was significantly different between si-lncRNA SNHG10 and control group. Conclusions The immune-related lncRNAs prognostic signature provided some potential biomarkers and molecular mechanisms in HBV-related HCC.
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Project description:BackgroundHepatocellular carcinoma (HCC) is a life-threatening and refractory malignancy with poor outcome. Genetic mutations are the hallmark of cancer. Thus far, there is no comprehensive prognostic model constructed by mutation-gene transcriptome in HCC. The prognostic value of mutation-gene signature in HCC remains elusive.MethodsRNA expression profiles and the corresponding clinical information were recruited from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was employed to establish gene signature. Kaplan-Meier curve and time-dependent receiver operating characteristic curve were implemented to evaluate the prognostic value. The Wilcoxon test was performed to analyze the expression of immune checkpoint genes, cell cycle genes, and tumor drug resistance genes in different risk groups. Finally, quantitative real-time PCR (qRT-RCR) and immunohistochemistry (IHC) were performed to validate the mRNA and protein expression between HCC and adjacent nontumorous tissues in an independent cohort.ResultsA prognostic model consisting of five mutated genes was established by LASSO Cox regression analysis. The prognostic model classified patients into high- and low-risk groups. Compared with the low-risk group, patients in the high-risk group had significantly worse survival results. The prognostic model can accurately predict the overall survival of HCC patients and predict overall survival more accurately when combined with stage. Furthermore, the immune checkpoint genes, cell cycle genes, and tumor drug resistance genes were higher expressed in the high-risk group compared in the low-risk group. In addition, the expression level of prognostic signature genes was validated in an independent sample cohort, which was consistent with RNA sequencing expression in the TCGA database.ConclusionThe prediction model of HCC constructed using mutation-related genes is of great significance for clinical decision making and the personalized treatment of patients with HCC.
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Project description:Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC.
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Project description:Hepatocellular carcinoma (HCC) has an extremely poor prognosis and is one of the most common malignancies worldwide. Immune checkpoint suppression has become the most effective treatment option for liver cancer. The strategies used for immune checkpoint inhibitor targeting cancer therapies have been affected by some significant successes, including blocking the advanced-stage malignant tumor by death protein 1 (PD-1)/programmed cell death ligand (PDL-1), and cytotoxic T-lymphocyte antigen-4 (CTLA4) pathways. T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is an immune checkpoint that participates in tumor immune surveillance. Mainly expressed on T cells, natural killer (NK) cells, and other antigen-presenting cells (APCs), it diminishes cytokine production and exhibits strong suppressive properties. TIGIT achieves a more active antitumor immune response and highlights a pivotal role for cancer immunotherapy. Preclinical studies have found inhibitory effects using a targeted approach. Monotherapy targeting TIGIT or in combination with anti-PD-1/PD-L1 monoclonal antibodies for the treatment of patients with advanced solid malignancies have demonstrated improved antitumor immune responses. Due to the high tumor heterogeneity of liver cancer, immune checkpoint suppression therapy still needs further exploration. Therefore, we provide insights into the characteristics of TIGIT and the immune system in HCC.
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