Dataset Information

Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma.

ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare but highly aggressive thoracic malignancy. ESTIMATE algorithm-derived immune scores are commonly used to quantify the immune and stromal components in tumors. Thus, this algorithm may help determine the tumor microenvironment (TME)-related gene expression profile associated with tumor immunity. This study aimed at mining public databases to determine a potential correlation between differentially expressed genes (DEGs) and survival in patients with MPM. We categorized patients from the Gene Expression Omnibus database according to their immune/stromal scores into high- and low-score groups. Functional enrichment analysis and the construction of protein-protein interaction networks showed that the DEGs identified were primarily involved in the TME. Furthermore, we validated these genes in an independent cohort of patients with MPM from The Cancer Genome Atlas database. DEG analysis showed that 29 DEGs were cancer driver genes. Subsequently, 14 TME-related genes, which have been previously neglected, were shown to exhibit significant prognostic potential in MPM. In conclusion, immune/stromal scores are novel predictors of a poor prognosis in patients with MPM. We identified DEGs that are involved in immunity against MPM and may contribute to patient survival. Owing to their potential as prognostic factors for MPM, these 14 TME-related genes need to be studied in detail in the future.

SUBMITTER: Xu X

PROVIDER: S-EPMC7526499 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma.

Xu Xiaoling X Cheng Lei L Fan Yun Y Mao Weimin W

Frontiers in oncology 20200916

Malignant pleural mesothelioma (MPM) is a rare but highly aggressive thoracic malignancy. ESTIMATE algorithm-derived immune scores are commonly used to quantify the immune and stromal components in tumors. Thus, this algorithm may help determine the tumor microenvironment (TME)-related gene expression profile associated with tumor immunity. This study aimed at mining public databases to determine a potential correlation between differentially expressed genes (DEGs) and survival in patients with ...[more]

PMID: 33042835

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Project description:BackgroundThe combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts.MethodsThe discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database.ResultsMost patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients [hazard ratio (HR), 3.42 (1.15-10.16)] with low tumor mesothelin levels [HR, 2.58 (1.09-6.10)] and high PD-L1 and low infiltration of T cells CD4+ [HR, 3.81 (1.58-9.18)]. In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival.ConclusionTumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.

Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.

Dataset Information

Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma.

Publications

Tumor Microenvironment-Associated Immune-Related Genes for the Prognosis of Malignant Pleural Mesothelioma.

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