scholarly journals Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Clément Meiller ◽  
François Montagne ◽  
Theo Z. Hirsch ◽  
Stefano Caruso ◽  
Julien de Wolf ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Immunological Synapse ◽  
Side Wall ◽  
Molecular Classification ◽  
Suppressor Gene ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Methylome Analysis

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.

scholarly journals Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2454
Author(s):  
Federica Torricelli ◽  
Filippo Lococo ◽  
Teresa Severina Di Stefano ◽  
Eugenia Lorenzini ◽  
Simonetta Piana ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Deep Sequencing ◽  
Validation Cohort ◽  
Genetic Alterations ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Specific Subset ◽  
Validation Set ◽  
Custom Panel ◽  
Deep Sequencing Analysis

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients’ survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients’ risk stratification.

scholarly journals Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival

2020 ◽  
Vol 14 (6) ◽  
pp. 1207-1223 ◽  
Author(s):  
Lisa Quetel ◽  
Clément Meiller ◽  
Jean‐Baptiste Assié ◽  
Yuna Blum ◽  
Sandrine Imbeaud ◽  
...  
Keyword(s):  
Overall Survival ◽  
Malignant Pleural Mesothelioma ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Pleural Mesothelioma

scholarly journals Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 915
Author(s):  
Fabio Nicolini ◽  
Martine Bocchini ◽  
Davide Angeli ◽  
Giuseppe Bronte ◽  
Angelo Delmonte ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Neutralizing Antibodies ◽  
Specific Binding ◽  
Screening Methods ◽  
Human Antibody ◽  
Pleural Mesothelioma ◽  
Full Potential ◽  
Sequencing Analysis ◽  
Human Antibodies ◽  
Promising Therapeutic Approach

Immunotherapy is the most promising therapeutic approach against malignant pleural mesothelioma (MPM). Despite technological progress, the number of targetable antigens or specific antibodies is limited, thus hindering the full potential of recent therapeutic interventions. All possibilities of finding new targeting molecules must be exploited. The specificity of targeting is guaranteed by the use of monoclonal antibodies, while fully human antibodies are preferred, as they are functional and generate no neutralizing antibodies. The aim of this review is to appraise the latest advances in screening methods dedicated to the identification and harnessing of fully human antibodies. The scope of identifying useful molecules proceeds along two avenues, i.e., through the antigen-first or binding-first approaches. The first relies on screening human antibody libraries or plasma from immunized transgenic mice or humans to isolate binders to specific antigens. The latter takes advantage of specific binding to tumor cells of antibodies present in phage display libraries or in responders’ plasma samples without prior knowledge of the antigens. Additionally, next-generation sequencing analysis of B-cell receptor repertoire pre- and post-therapy in memory B-cells from responders allows for the identification of clones expanded and matured upon treatment. Human antibodies identified can be subsequently reformatted to generate a plethora of therapeutics like antibody-drug conjugates, immunotoxins, and advanced cell-therapeutics such as chimeric antigen receptor-transduced T-cells.

scholarly journals Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

2020 ◽  
Vol 14 ◽  
pp. 175346662093577 ◽  
Author(s):  
Jia Hu ◽  
Baoshi Zhang ◽  
Fangfang Yao ◽  
Yan Fu ◽  
Dianjun Chen ◽  
...  
Keyword(s):  
Case Report ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Pleural Mesothelioma ◽  
Sequencing Analysis ◽  
Alk Rearrangement ◽  
Alk Inhibitors ◽  
Anaplastic Lymphoma ◽  
Incremental Step

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection of EML4-ALK rearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutations ALK I1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

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

2020 ◽  
Vol 21 (15) ◽  
pp. 1606-1612 ◽  
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.

scholarly journals OA02.07 Characterization of the Tumor Microenvironment and Investigation of Immune Checkpoint Expression in Malignant Pleural Mesothelioma

2017 ◽  
Vol 12 (1) ◽  
pp. S249-S250
Author(s):  
Elly Marcq ◽  
Vasiliki Siozopoulou ◽  
Jorrit De Waele ◽  
Jonas Van Audenaerde ◽  
Karen Zwaenepoel ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Malignant Pleural Mesothelioma ◽  
Immune Checkpoint ◽  
Pleural Mesothelioma
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