Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma

Our plain-English summary of Immune Microenvironment and Genetics in Malignant Pleural Mesothelioma, by B. Wadowski, R. Bueno, A. De Rienzo (Frontiers in Oncology, 2021).

The study

• Authors: B. Wadowski, R. Bueno, A. De Rienzo
• Journal: Frontiers in Oncology
• Published: 2021;11:684025
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2021 Wadowski, Bueno and De Rienzo.

In plain English

This was a mini review of published research on malignant pleural mesothelioma. The authors looked at how the tumor's genetics, including epigenetics and gene activity, relate to the immune cells in and around the tumor. It reported no new patient data. The authors noted that few patients respond to current checkpoint inhibitor immunotherapy and that reliable markers to predict response are lacking. Summarizing other studies, they wrote that mesothelioma generally shows an immunosuppressive environment driven by M2 macrophages, that more M2 macrophages relative to lymphocytes has been linked to shorter survival, and that higher PD-L1 expression has been associated with shorter survival. They described a study of blood DNA methylation in mesothelioma patients and healthy controls, which supported the hypothesis that such changes may be associated with asbestos exposure. They also described a link between BAP1 loss and immune activity that was found in peritoneal mesothelioma but not shown in pleural mesothelioma. The authors concluded that several gaps remain before genetic signatures can be linked to the immune environment to predict outcomes and guide therapy, and that causal relationships still need to be tested.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Mini review of published literature (no new data collected by the authors)
• Who was studied: Published studies of malignant pleural mesothelioma tumors, cell lines and gene-expression datasets, plus one study of peritoneal mesothelioma. The review does not state how many studies were included or how they were selected.
• Exposure: Not an exposure study. As background, the review states, citing another source, that MPM is associated with asbestos exposure in 70-90% of cases. No fiber types are named.
• Main results:
  • Background stated by the review: few MPM patients respond to current checkpoint inhibitor regimens, and reliable predictive biomarkers for response are lacking.
  • Summarizing cited studies, the review states that MPM generally displays an immunosuppressive microenvironment mediated by M2 macrophages.
  • Per cited studies, across histologic subtypes, a higher balance of M2 macrophages relative to lymphocyte infiltration has been shown to predict shorter survival.
  • Per cited studies, a higher proportion of CD8 relative to CD4 T cells has been associated with shorter survival. One early study of tumors removed after neoadjuvant chemotherapy instead showed a trend toward longer survival with high CD8 cells.
  • Per cited studies, higher PD-L1 expression is associated with shorter survival, and non-epithelioid tumors show higher PD-L1 expression than epithelioid tumors.
  • A cited study compared 163 MPM patients with 137 healthy controls and found differential methylation of immune-related genes. The review states these data supported the hypothesis that DNA methylation and tumor microenvironment changes may be associated with asbestos exposure.
  • A cited study of 19 peritoneal mesothelioma tumors linked BAP1 loss to an inflammatory tumor microenvironment. The review states this finding was not supported by the TCGA analysis in pleural mesothelioma.
• The authors' conclusion: The authors concluded that several gaps remain in linking genetic signatures to the tumor immune microenvironment, especially for predicting clinical outcomes and guiding therapy. They expressed the view that a full understanding of this association will lead to improved prognostication and outcomes for MPM patients.
• Limitations the authors state:
  • The authors state that there is significant variability even among histologically similar tumors, and that further work is needed to explore how this variability may affect treatment response.
  • The authors state that further work is needed to assess whether the reported genetic and epigenetic findings have causal relationships with specific changes in the tumor microenvironment.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, PD-L1, Clinical Trial, Next-Generation Sequencing (NGS).

Related studies

• Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma — S. Hiltbrunner, L. Mannarino, et al. (2021)
• Priming the tumor immune microenvironment with chemo(radio)therapy: A systematic review across tumor types — T. van den Ende, H.G. van den Boorn, et al. (2020)
• The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy — G.J. Chu, N. van Zandwijk, et al. (2019)
• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma — S. Mitra, M. Lauss, et al. (2020)
• Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy — J. Harber, T. Kamata, et al. (2021)

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