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

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

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Prognostic role of PD-L1 in malignant pleural mesothelioma: unraveling the complexity of the tumor microenvironment in mesothelioma

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2020.12.052 ◽

2021 ◽

Author(s):

Marc de Perrot

Keyword(s):

Tumor Microenvironment ◽

Malignant Pleural Mesothelioma ◽

Pleural Mesothelioma ◽

Prognostic Role

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Progress in the Understanding of the Immune Microenvironment and Immunotherapy in Malignant Pleural Mesothelioma

Current Drug Targets ◽

10.2174/1389450121666200719011234 ◽

2020 ◽

Vol 21 (15) ◽

pp. 1606-1612 ◽

Cited By ~ 1

Author(s):

Lei Cheng ◽

Na Li ◽

Xiao-ling Xu ◽

Wei-Min Mao

Keyword(s):

Tumor Microenvironment ◽

Malignant Pleural Mesothelioma ◽

Asbestos Exposure ◽

Extrapleural Pneumonectomy ◽

Pleural Mesothelioma ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Mechanism Of Carcinogenesis ◽

Cycle Regulation ◽

The Relationship

Malignant pleural mesothelioma (MPM) is a remarkably aggressive thoracic malignancy with a limited survival of only 5-12 months. However, MPM still remains unresponsive to conventional standards of treatment, including pleurectomy and decortication, extrapleural pneumonectomy for resectable disease with or without chemotherapy, and/or radiation therapy. The mechanism of carcinogenesis has not been fully elucidated, although approximately 80% of cases can still be linked to asbestos exposure. The tumor immune microenvironment (TME) has been proven to play an important role in MPM pathogenesis and treatment outcomes. Several molecular pathways have been implicated in the MPM tumor microenvironment, such as angiogenesis, apoptosis, cell cycle regulation, and stromal processes. Immunotherapy has already shown promising results in other thoracic solid tumors, such as non-small-cell lung cancer (NSCLC). However, immunotherapy has shown less convincing results in MPM than in melanoma and NSCLC. A multicenter, randomized trial (DETERMINE) proved that immune checkpoint inhibition using tremelimumab, an anti-cytotoxic T lymphocyteassociated protein 4 (CTLA-4) antibody, failed to improve median overall survival. Therefore, it is important to explore the relationship between the characteristics of the tumor microenvironment and immunotherapy. Here, we review the heterogeneity of the TME and the progress in the understanding of the immune microenvironment and immunotherapy in MPM to explore the mechanisms of resistance to immunotherapy.

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Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

Frontiers in Oncology ◽

10.3389/fonc.2021.684025 ◽

2021 ◽

Vol 11 ◽

Author(s):

Benjamin Wadowski ◽

Raphael Bueno ◽

Assunta De Rienzo

Keyword(s):

Malignant Pleural Mesothelioma ◽

Current Evidence ◽

Small Subset ◽

Pleural Mesothelioma ◽

Checkpoint Inhibition ◽

Immune Microenvironment ◽

Molecular Features ◽

Immune Related Genes ◽

Next Generation Sequencing Ngs ◽

Review Current

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options beyond surgery and cytotoxic chemotherapy. The success of immune checkpoint inhibition has been found to correlate with expression of immune-related genes such as CD274 (PD-L1) in lung and other solid cancers. However, only a small subset of MPM patients respond to checkpoint inhibition, and this response has been varied and unpredictable across several clinical trials. Recent advances in next-generation sequencing (NGS) technology have improved our understanding of the molecular features of MPM, also with respect to its genetic signature and how this impacts the immune microenvironment. This article will review current evidence surrounding the interplay between MPM genetics, including epigenetics and transcriptomics, and the immune response.

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