Dataset Information

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage.

ABSTRACT: Spontaneous tumor hemorrhage (TH) is frequently observed in solid tumors including human hepatocellular carcinoma (HCC). TH implies fast-growing and worse tumor immunological microenvironment; however, the underlying mechanism remains largely unknown. CLEC1B is a signature gene highly associated with tumor progression. PD-L1 expression is a key biomarker predictive of immune checkpoint therapies, which showed astonishing effect on various types of tumor. We assume that, in HCC, TH may closely associate with the expression of these two molecules. In this study, 136 patients with HCC were enrolled. qRT-PCR showed that CLEC1B expression is significantly lower in HCC tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that PD-L1high and CLEC1Blow expressions were significantly correlated with TH and clinicopathological features indicating worse HCC progression. According to univariate/multivariate analysis, a combination of PD-L1high and CLEC1Blow expression was an independent prognostic factor indicating the poor outcome. The prognostic value of PD-L1high and CLEC1Blow was validated by Cox proportional-hazard analyses. Collectively, tumor with TH is closely associated with CLEC1Blow & PD-L1high expression, which may imply high response of PD-L1/PD-1 immune checkpoint therapies. CLEC1B may be a potential therapeutic target for PD-L1/PD-1 immunotherapy. PD-L1high and CLEC1Blow can be a valuable prognosis factor implying worse clinical outcomes.

SUBMITTER: Hu K

PROVIDER: S-EPMC5884195 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage.

Hu Kuan K Wang Zhi-Ming ZM Li Juan-Ni JN Zhang Sai S Xiao Zhong-Fu ZF Tao Yi-Ming YM

Translational oncology 20180308 2

Spontaneous tumor hemorrhage (TH) is frequently observed in solid tumors including human hepatocellular carcinoma (HCC). TH implies fast-growing and worse tumor immunological microenvironment; however, the underlying mechanism remains largely unknown. CLEC1B is a signature gene highly associated with tumor progression. PD-L1 expression is a key biomarker predictive of immune checkpoint therapies, which showed astonishing effect on various types of tumor. We assume that, in HCC, TH may closely as ...[more]

PMID: 29525632

Similar Datasets

Project description:Hepatocellular carcinoma (HCC) has an increasing incidence worldwide, and the global 5-year survival rate ranges from 5-30%. In China, HCC seriously threatens the nation's health; the incidence of HCC ranks fourth among all theriomas, and the mortality rate is the third highest worldwide. The main therapies for HCC are surgical treatment or liver transplantation; however, most patients with HCC will experience postoperative recurrence or metastasis, eventually resulting in mortality. As for advanced or unresectable HCC, the current appropriate treatment strategy is transarterial chemoembolization; however, limited therapeutic effect and natural or acquired drug resistance affect the efficacy of this approach. Previous studies have demonstrated that PD-L1 expression on host cells and myeloid cells plays an important role in PD-L1 blocked-mediated tumor regression. Thus, further research on programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) is required. Countries including the United States, France, Britain and China have developed PD-1/PD-L1 blockers, including nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, toripalimab, sintilimab and camrelizumab. Notably, all of these blockers have therapeutic effect and influencing factors in HCC. Factors that influence the clinical outcome of PD-1 have also been discovered, such as inflammatory genes, specific receptors and signaling pathways. The discovery of these factors will help to identify novel methods, such as combination treatment, to decrease the influence of other factors on the efficacy of PD-1/PD-L1. Sorafenib and lenvatinib have been approved for first-line treatment for patients with advanced HCC. When first-line treatment frequently fails, pembrolizumab and ipilimumab plus nivolumab are used following sorafenib (but not lenvatinib) treatment in advanced HCC. Thus, tumor immunotherapy using PD-1/PD-L1 blockers exhibits promising outcomes for the treatment of HCC, and more novel PD-1/PD-L1 inhibitors are being developed to fight against this disease. The present review discusses the clinical results and influencing factors of PD-1/PD-L1 inhibitors in HCC to provide insight into the development and optimization of PD-1/PD-L1 inhibitors in the treatment of HCC.

Project description:LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It's essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort (n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.

Project description:Classical Hodgkin lymphomas (cHLs) include small numbers of malignant Reed-Sternberg cells within an extensive but ineffective inflammatory/immune cell infiltrate. In cHL, chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through Janus kinase 2-signal transducers and activators of transcription signaling. The unique composition of cHL limits its analysis with high-throughput genomic assays. Therefore, the precise incidence, nature, and prognostic significance of PD-L1/PD-L2 alterations in cHL remain undefined.We used a fluorescent in situ hybridization assay to evaluate CD274/PD-L1 and PDCD1LG2/PD-L2 alterations in 108 biopsy specimens from patients with newly diagnosed cHL who were treated with the Stanford V regimen and had long-term follow-up. In each case, the frequency and magnitude of 9p24.1 alterations-polysomy, copy gain, and amplification-were determined, and the expression of PD-L1 and PD-L2 was evaluated by immunohistochemistry. We also assessed the association of 9p24.1 alterations with clinical parameters, which included stage (early stage I/II favorable risk, early stage unfavorable risk, advanced stage [AS] III/IV) and progression-free survival (PFS).Ninety-seven percent of all evaluated cHLs had concordant alterations of the PD-L1 and PD-L2 loci (polysomy, 5% [five of 108]; copy gain, 56% [61 of 108]; amplification, 36% [39 of 108]). There was an association between PD-L1 protein expression and relative genetic alterations in this series. PFS was significantly shorter for patients with 9p24.1 amplification, and the incidence of 9p24.1 amplification was increased in patients with AS cHL.PD-L1/PD-L2 alterations are a defining feature of cHL. Amplification of 9p24.1 is more common in patients with AS disease and associated with shorter PFS in this series. Further analyses of 9p24.1 alterations in patients treated with standard cHL induction regimens or checkpoint blockade are warranted.

Project description:Neutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+ neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+ neutrophils in hepatocellular carcinoma. Neutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+ neutrophil infiltration. Further in vivo assays were used for verification. Lenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+ neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+ neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+ neutrophil and promoted the antitumor effect of lenvatinib. PD-L1+ neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+ neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.

Dataset Information

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage.

Publications

CLEC1B Expression and PD-L1 Expression Predict Clinical Outcome in Hepatocellular Carcinoma with Tumor Hemorrhage.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets