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Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1

ABSTRACT: Background and Aim Immune checkpoint inhibitors are promising agents for the treatment of hepatocellular carcinomas (HCC) refractory to conventional therapies. To enhance the efficacy of this treatment, immunological and molecular characteristics of HCC with programmed cell death ligand 1 (PD-L1) should be explored. Methods Clinical backgrounds, PD-L1 expression, and the amount of CD8+ tumor-infiltrating mononuclear cells (TIMCs) were analyzed in 154 HCCs. The expression of 3 stem cell markers and co-inhibitory receptors on tumor cells and TIMCs, respectively, were examined by immunohistochemical analysis. Somatic mutations in the 409 cancer-associated genes and TERT promoter were determined; HCCs were classified based on the presence of gene alterations affecting the 8 oncogenic pathways. The results were validated using the dataset from the Cancer Genome Atlas. Results The expression of PD-L1 in the HCCs was positively correlated with progressive tumor features, the presence of cytokeratin 19 (CK19), Sal-like protein 4 (SALL4), and the mutations of genes involving the phosphatidyl inositol 3-kinase (PI3K)-Akt pathway. Although CD8+ cells were densely infiltrated in PD-L1-positive tumors, these TIMCs frequently expressed multiple co-inhibitory receptors. However, a subset of PD-L1-positive tumors characterized by activating mutations of the PI3K-Akt pathway showed a low degree of TIMCs. Conversely, PD-L1-negative HCCs were associated with mutations in the ?-catenin pathway and a small number of TIMCs, although the expression of co-inhibitory receptors was rare. Conclusions PD-L1-positive HCCs frequently showed an inflamed phenotype with stem cell features; a subset of PD-L1-positive HCCs with mutations in the PI3K-Akt pathway showed a non-inflamed phenotype. In HCCs with dense infiltration of TIMCs, CD8+ cells expressed multiple co-inhibitory receptors, suggesting T cell exhaustion. On the other hand, PD-L1-negative HCCs showed mutations leading to ?-catenin activation and exhibited a non-inflamed background. These characteristics should be taken into consideration for developing novel combination therapies using immune checkpoint inhibitors.

SUBMITTER: Nishida N

PROVIDER: S-EPMC7506256 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Project description:The quantity of programmed cell death-ligand 1 (PD-L1) is regarded as a predicting factor of clinical response to anti-PD-1 axis immunotherapy. However, the expression of PD-L1 and its prognostic value in hepatocellular carcinoma (HCC) patients remain debated. Meanwhile, the molecular features of PD-1's other ligand, namely PD-L2, as well as its correlation with clinicopathological parameters and HCC tumor microenvironment (TME), are still poorly understood. In this study, immunohistochemistry (IHC) data from 304 HCC patients were used to determine the clinicopathological features of PD-L1 and PD-L2 and their correlation with CD8+ T cells in HCC. Moreover, fresh clinical HCC samples were used to identify the immune cell subtypes expressing PD-L1 and PD-L2. By using The Cancer Genome Atlas (TCGA) dataset, we further assessed the correlation between mutation signature, copy number variation (CNV), number of neoepitopes, immune gene expression, immune/stromal cell infiltration to the expression of PD-L1 and PD-L2. While membrane expression of PD-L2 was observed in 19.1% of tumor samples, no obvious expression of PD-L1 was detected on tumor cell membranes. High expression of PD-L2 on tumor membranes and PD-L1 in immune stroma were both significantly associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes. Flow cytometry analysis and immunofluorescence showed that macrophages were the main immune cell subtype expressing both PD-L1 and PD-L2. Moreover, positive expression of PD-Ls was correlated with higher CD8+ T cells infiltration in immune stroma. CNV analysis showed a similarity between PD-L1 and PD-L2 in affecting gene expression. In addition, higher levels of PD-Ls correlated with higher expression of immune related genes, enhanced cytolytic activity, and larger proportions of immune/stromal cell infiltration. Collectively, our study reveals the impact of both PD-L1 and PD-L2 on the HCC tumor microenvironment for the first time, providing insight for new therapeutic options.

Project description:BackgroundProgrammed cell death ligand 1 (PD-L1), which is highly expressed in a variety of malignant tumors, is closely related to clinicopathological features and prognosis. However, there are few studies on the potential effects of PD-L1 on thyroid carcinoma, the incidence of which has shown an upward trend worldwide. This study aimed to explore the association between PD-L1 expression and clinicopathological features and prognosis of thyroid cancer.MethodsAn elaborate retrieval was performed using Medline, PubMed, Cochrane Library, EMBASE, Web of Science, WanFang databases, and China National Knowledge Infrastructure to determine the association between PD-L1 expression and disease-free survival (DFS), overall survival (OS), and clinicopathological features in patients with thyroid cancer. Study selection, data extraction, risk assessment, and data synthesis were performed independently by 2 reviewers. In this meta-analysis, RevMan 5.3 and Stata 15.1 were used for bias risk assessment and data synthesis.ResultsAfter a detailed search, 2546 cases reported in 13 articles were included in this meta-analysis. The outcomes revealed that high expression of PD-L1 in patients with thyroid cancer was associated with poor DFS (hazard ratio [HR] = 3.37, 95% confidence interval [CI] 2.54-4.48, P < .00001) and OS (HR = 2.52, 95% CI: 1.20-5.32, P = .01). High PD-L1 expression was associated with tumor size ≥2 cm, tumor recurrence, extrathyroidal extension, concurrent thyroiditis, unifocal tumor, and absence of psammoma body (P < .05). Subgroup analysis showed that positive expression of PD-L1 was related to poor prognosis for DFS of non-medullary thyroid carcinoma, and the overexpression of PD-L1 in differentiated thyroid carcinoma (DTC) was related to tumor recurrence, concurrent thyroiditis, extrathyroidal extension, unifocal DTC, late stage DTC, and BRAFV600E mutation in DTC.ConclusionPD-L1 is a significant predictor of prognosis and malignancy of thyroid cancer (especially DTC), and PD-L1 inhibitors may be a promising therapeutic option for refractory thyroid cancer in the future.

Project description:ObjectiveProgrammed death-ligand 1 (PD-L1) expression in the tumor microenvironment (TME) has been reported to be related to prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC is unclear.Patients and methodsPatients with HCC who received sorafenib for advanced disease at National Taiwan University Hospital, Taipei, Taiwan, and who had paired HCC tissues obtained before and after sorafenib treatment were included in the study group. HCC patients not treated with sorafenib who had paired primary and recurrent or metastatic tissues were identified as the reference group. The membrane PD-L1 staining, detected by immunohistochemistry (IHC) using SP142 antibody, was semiquantitatively scored in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). Additional IHC assays were employed to characterize the PD-L1-expressing ICs.ResultsTwenty-three advanced HCC patients with pre- and post-sorafenib paired HCC tissues were included in the study group. The median duration of sorafenib treatment was 4.3 months (range: 1.3-18.7). PD-L1 expression in ICs was significantly higher in post-sorafenib HCC tissues than in pre-sorafenib HCC tissues (pre-sorafenib vs. post-sorafenib IHC 0/1/2/3: 11/5/5/2 vs. 5/5/2/11, p = 0.016). However, PD-L1 expression in TCs was not significantly different between pre- and post-sorafenib tissues (IHC 0/1/2/3: 19/2/0/2 vs. 14/5/0/4, p = 0.094). In the reference group of 44 patients not treated with sorafenib, PD-L1 expression in ICs and TCs was not significantly different between the paired primary and metastatic HCC tissues. By performing IHC double staining with PD-L1 and CD68, we found the PD-L1-expressing ICs were mainly CD68-positive macrophages. PD-L1 expression levels of pre- and post-sorafenib tissues were not associated with patients' overall survival or duration of sorafenib treatment.ConclusionsPD-L1 expression in ICs was significantly increased in post-sorafenib HCC tissues. The mechanisms and clinical significance of this observation warrants further investigation.

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Association between Genetic and Immunological Background of Hepatocellular Carcinoma and Expression of Programmed Cell Death-1

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