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 Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2564
Author(s):  
Francesca Napoli ◽  
Angela Listì ◽  
Vanessa Zambelli ◽  
Gianluca Witel ◽  
Paolo Bironzo ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Current Knowledge ◽  
Asbestos Exposure ◽  
Cellular Damage ◽  
Pleural Mesothelioma ◽  
Immune Microenvironment ◽  
Chronic Inflammatory Response ◽  
Inflammatory Microenvironment ◽  
Tumor Immune Microenvironment

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive disease that arises from pleural mesothelial cells, characterized by a median survival of approximately 13–15 months after diagnosis. The primary cause of this disease is asbestos exposure and the main issues associated with it are late diagnosis and lack of effective therapies. Asbestos-induced cellular damage is associated with the generation of an inflammatory microenvironment that influences and supports tumor growth, possibly in association with patients’ genetic predisposition and tumor genomic profile. The chronic inflammatory response to asbestos fibers leads to a unique tumor immune microenvironment (TIME) composed of a heterogeneous mixture of stromal, endothelial, and immune cells, and relative composition and interaction among them is suggested to bear prognostic and therapeutic implications. TIME in MPM is known to be constituted by immunosuppressive cells, such as type 2 tumor-associated macrophages and T regulatory lymphocytes, plus the expression of several immunosuppressive factors, such as tumor-associated PD-L1. Several studies in recent years have contributed to achieve a greater understanding of the pathogenetic mechanisms in tumor development and pathobiology of TIME, that opens the way to new therapeutic strategies. The study of TIME is fundamental in identifying appropriate prognostic and predictive tissue biomarkers. In the present review, we summarize the current knowledge about the pathological characterization of TIME in MPM.

Case 13.8

2014 ◽  
pp. 628-629
Author(s):  
Christine U. Lee ◽  
James F. Glockner
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
The United States ◽  
Extrapleural Pneumonectomy ◽  
Parietal Pleura ◽  
Pleural Mesothelioma ◽  
Pleural Plaques ◽  
Abnormal Chest ◽  
Left Pleura ◽  
Histologic Subtypes

62-year-old man with shortness of breath and an abnormal chest CT Axial 3D SPGR postgadolinium images (Figure 13.8.1) demonstrate diffuse thickening and enhancement of the left pleura, with a few minimally enhancing, focal right-sided pleural plaques. Malignant pleural mesothelioma Malignant pleural mesothelioma is a rare neoplasm that originates from the mesothelial cells lining the visceral and parietal pleura. The incidence of malignant pleural mesothelioma in the United States is 15 cases per million; there is a strong correlation with asbestos exposure. Malignant pleural mesothelioma is divided into 3 histologic subtypes: epithelial (55%-65%), sarcomatoid (10%-15%), and mixed (20%-35%). Patients with epithelial malignant pleural mesothelioma have the best prognosis, and among those with limited disease who undergo extrapleural pneumonectomy (removal of the pleura, lung, hemidiaphragm, and part of the pericardium), survival is longer (5-year survival, 39%) than among all patients (median survival, 8-18 months after diagnosis)....

scholarly journals Multimodality treatment of malignant pleural mesothelioma

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1681 ◽  
Author(s):  
Lawek Berzenji ◽  
Paul Van Schil
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Multimodality Treatment ◽  
Treatment Modalities ◽  
Surgical Approaches ◽  
Extrapleural Pneumonectomy ◽  
Pleural Mesothelioma ◽  
Treatment Approaches ◽  
Definitive Answer ◽  
Platinum Based Chemotherapy

Malignant pleural mesothelioma (MPM) is a rare disease of the pleura and is largely related to asbestos exposure. Despite recent advancements in technologies and a greater understanding of the disease, the prognosis of MPM remains poor; the median overall survival rate is about 6 to 9 months in untreated patients. The main therapeutic strategies for MPM are surgery, chemotherapy, and radiation therapy (RT). The two main surgical approaches for MPM are extrapleural pneumonectomy (EPP), in which the lung is removed en bloc, and pleurectomy/decortication, in which the lung stays in situ. Chemotherapy usually consists of a platinum-based chemotherapy, such as cisplatin, often combined with a folate antimetabolite, such as pemetrexed. More recently, immunotherapy has emerged as a possible therapeutic strategy for MPM. Evidence suggests that single-modality treatments are not an effective therapeutic approach for MPM. Therefore, researchers have started to explore different multimodality treatment approaches, in which often combinations of surgery, chemotherapy, immunotherapy, and RT are investigated. There is still no definitive answer to the question of which multimodality treatment combinations are most effective in improving the poor prognosis of MPM. Research into the effects of trimodality treatment approaches have found that radical approaches such as EPP and hemithoracic RT post-EPP are less effective than was previously assumed. In general, there are still a great number of unanswered questions and unknown factors regarding the ideal treatment approach for MPM. Hopefully, more research into multimodality therapy will provide insight into which combination of treatment modalities is most effective.

scholarly journals Cancer-directed surgery in malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication

2021 ◽  
Author(s):  
Brian Housman ◽  
Andrea S. Wolf
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Morbidity Rate ◽  
Extrapleural Pneumonectomy ◽  
High Morbidity ◽  
Pleural Mesothelioma ◽  
Solid Malignancy ◽  
Future Treatment ◽  
High Morbidity Rate ◽  
Therapeutic Alternatives

Malignant pleural mesothelioma (MPM) is a primary solid malignancy related to inhalational asbestos exposure. Despite advances in therapy, MPM remains challenging to treat with a post-treatment survival of only 15% at 5-year. In recent years, extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives. In this review, we will discuss both procedures, outcomes, ongoing studies, and the roles of surgery in the future treatment of this disease.

scholarly journals The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3205
Author(s):  
Anne-Laure Désage ◽  
Georgia Karpathiou ◽  
Michel Peoc’h ◽  
Marios E. Froudarakis
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Median Overall Survival ◽  
Asbestos Exposure ◽  
Immune Checkpoints ◽  
Pleural Mesothelioma ◽  
M2 Macrophages ◽  
Immune Microenvironment ◽  
Cytotoxic Effects ◽  
Promising Treatment ◽  
Infiltrating Lymphocytes

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.

scholarly journals Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

2016 ◽  
Vol 6 (1) ◽  
pp. e1261241 ◽  
Author(s):  
Elly Marcq ◽  
Vasiliki Siozopoulou ◽  
Jorrit De Waele ◽  
Jonas van Audenaerde ◽  
Karen Zwaenepoel ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Immune Checkpoints ◽  
Pleural Mesothelioma ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

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.

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