Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

Wadowski, Benjamin; Bueno, Raphael; Rienzo, Assunta De

doi:10.3389/fonc.2021.684025

Cited by 7 publications

(5 citation statements)

References 52 publications

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“…In the study, a higher number of PD-1 + CTLA-4 + CD8 + T cells was found in a subtype and more ICOS + -CTLA4 + T-regs and PD-1 + TAMs in the other one, suggesting a different response to immune-checkpoint inhibitors (ICIs) [ 130 ]. Additionally, increased macrophage infiltration was detected in the non-epithelioid MPM and a high ratio CD8 + /CD68 + was correlated with a worse prognosis [ 34 , 131 ]. Non-epithelioid subtypes were also associated with PD-L2 positivity, and they were more likely to have a high infiltration with TIM3+ lymphocytes.…”

Section: Intra-tumor Heterogeneity Within Mpm Subtypes and Tmementioning

confidence: 99%

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

Cersosimo

Barbarino

Lonardi

et al. 2021

Cancers

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Several studies have reported that cellular and soluble components of the tumor microenvironment (TME) play a key role in cancer-initiation and progression. Considering the relevance and the complexity of TME in cancer biology, recent research has focused on the investigation of the TME content, in terms of players and informational exchange. Understanding the crosstalk between tumor and non-tumor cells is crucial to design more beneficial anti-cancer therapeutic strategies. Malignant pleural mesothelioma (MPM) is a complex and heterogenous tumor mainly caused by asbestos exposure with few treatment options and low life expectancy after standard therapy. MPM leukocyte infiltration is rich in macrophages. Given the failure of macrophages to eliminate asbestos fibers, these immune cells accumulate in pleural cavity leading to the establishment of a unique inflammatory environment and to the malignant transformation of mesothelial cells. In this inflammatory landscape, stromal and immune cells play a driven role to support tumor development and progression via a bidirectional communication with tumor cells. Characterization of the MPM microenvironment (MPM-ME) may be useful to understand the complexity of mesothelioma biology, such as to identify new molecular druggable targets, with the aim to improve the outcome of the disease. In this review, we summarize the known evidence about the MPM-ME network, including its prognostic and therapeutic relevance.

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Section: Intra-tumor Heterogeneity Within Mpm Subtypes and Tmementioning

confidence: 99%

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

Cersosimo

Barbarino

Lonardi

et al. 2021

Cancers

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“…So far, the development of malignant mesothelioma in patients is mostly attributed to asbestos exposure. Asbestos fibers can cause chronic inflammation over time, leading to immune activation, inflammatory microenvironment, and changes in the genome and epigenome conducive to malignant transformation [ 6 ]. Additionally, pathogenesis of mesothelioma can be driven by a dysregulated translatome, as shown by polysome profiling [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, a recent study has shown differences in the internal morphology of asbestos ferruginous bodies (AFBs), which are a key indicator of asbestos-induced malignant mesothelioma, between smokers and non-smokers [ 4 ]. Recent advances in high-throughput technologies have helped reveal molecular cues, including genomic and epigenetic factors and their interplay with the immune response, that are relevant to mesothelioma development [ 5 , 6 ]. Additionally, preclinical models of mesothelioma have been useful in deciphering the disease’s pathogenesis and in developing new clinical interventions [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Malignant peritoneal mesotheliomas of rats induced by multiwalled carbon nanotubes and amosite asbestos: transcriptome and epigenetic profiles

Reamon-Buettner,

Rittinghausen,

Klauke

et al. 2024

Part Fibre Toxicol

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Background Malignant mesothelioma is an aggressive cancer that often originates in the pleural and peritoneal mesothelium. Exposure to asbestos is a frequent cause. However, studies in rodents have shown that certain multiwalled carbon nanotubes (MWCNTs) can also induce malignant mesothelioma. The exact mechanisms are still unclear. To gain further insights into molecular pathways leading to carcinogenesis, we analyzed tumors in Wistar rats induced by intraperitoneal application of MWCNTs and amosite asbestos. Using transcriptomic and epigenetic approaches, we compared the tumors by inducer (MWCNTs or amosite asbestos) or by tumor type (sarcomatoid, epithelioid, or biphasic). Results Genome-wide transcriptome datasets, whether grouped by inducer or tumor type, showed a high number of significant differentially expressed genes (DEGs) relative to control peritoneal tissues. Bioinformatic evaluations using Ingenuity Pathway Analysis (IPA) revealed that while the transcriptome datasets shared commonalities, they also showed differences in DEGs, regulated canonical pathways, and affected molecular functions. In all datasets, among highly- scoring predicted canonical pathways were Phagosome Formation, IL8 Signaling, Integrin Signaling, RAC Signaling, and TREM1 Signaling. Top-scoring activated molecular functions included cell movement, invasion of cells, migration of cells, cell transformation, and metastasis. Notably, we found many genes associated with malignant mesothelioma in humans, which showed similar expression changes in the rat tumor transcriptome datasets. Furthermore, RT-qPCR revealed downregulation of Hrasls, Nr4a1, Fgfr4, and Ret or upregulation of Rnd3 and Gadd45b in all or most of the 36 tumors analyzed. Bisulfite sequencing of Hrasls, Nr4a1, Fgfr4, and Ret revealed heterogeneity in DNA methylation of promoter regions. However, higher methylation percentages were observed in some tumors compared to control tissues. Lastly, global 5mC DNA, m6A RNA and 5mC RNA methylation levels were also higher in tumors than in control tissues. Conclusions Our findings may help better understand how exposure to MWCNTs can lead to carcinogenesis. This information is valuable for risk assessment and in the development of safe-by-design strategies.

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“…These results are consistent with reports of frequent association of PD-L1 protein expression and sarcomatoid mesotheliomas, poor prognosis, and increased lymphocytic inflammation. [78][79][80][81][82][83][84][85] TRAF mutations have been described in localized pleural mesothelioma 86 and in adenomatoid tumors of the genital tract 87 but have not yet been identified in thoracic adenomatoid tumors, although these are exceedingly rare with less than 20 reported in the thoracic region. [88][89][90] BAP1 mutations and genomic near haploidization have also been described in localized pleural mesothelioma.…”

Section: Differential Diagnoses Of Diffuse Pleural Mesothelioma: Thor...mentioning

confidence: 99%