Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

Our plain-English summary of Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma, by S. Hiltbrunner, L. Mannarino, M.B. Kirschner, et al (Frontiers in Oncology, 2021).

The study

• Authors: S. Hiltbrunner, L. Mannarino, M.B. Kirschner, I. Opitz, A. Rigutto, A. Laure, M. Lia, P. Nozza, A. Maconi, S. Marchini, M. D'Incalci, A. Curioni-Fontecedro, F. Grosso
• Journal: Frontiers in Oncology
• Published: 2021;11:660039
• Type of article: Review
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Copyright © 2021 Hiltbrunner, Mannarino, Kirschner, Opitz, Rigutto, Laure, Lia, Nozza, Maconi, Marchini, D’Incalci, Curioni-Fontecedro and Grosso.

In plain English

This article is a review, not a new study. The authors summarized published research on malignant pleural mesothelioma (MPM), which they stated is linked to asbestos exposure in up to 80% of cases. They described research suggesting that asbestos fibers in the pleura cause chronic inflammation involving the molecules HMGB1, TNF-alpha and IL-1beta. They also reviewed the immune cells found in these tumors; cited studies put macrophages at about 25-40% of immune cells. On inherited genes, they cited a report that mesotheliomas in carriers of BAP1 defects occur more often with no or low asbestos exposure, and a report that inherited BLM mutations promote mesothelioma, with risk further increased by asbestos exposure. They also covered tumor mutations, chromosome shattering (chromothripsis), microRNAs, DNA methylation and possible drug targets. They noted that evidence on PARP-inhibitor drugs was unclear and that no microRNA test was in routine clinical use. The authors concluded that nivolumab plus ipilimumab had been the most effective strategy, and that deeper knowledge of the disease's biology is crucial for improving patients' outcomes.

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: Review of published research (no new data collected)
• Who was studied: No study population. The review covers published research on malignant pleural mesothelioma (MPM), with some mention of malignant peritoneal mesothelioma.
• Exposure: Asbestos in general. The main text names no specific fiber types. The authors state that up to 80% of MPM cases are linked to asbestos, and they describe how asbestos fibers are thought to trigger inflammation and DNA damage in mesothelial cells.
• Main results:
  • From the studies reviewed, the authors summarized that the molecules HMGB1, TNF-alpha and IL-1beta appear to help drive the change of mesothelial cells into cancer after asbestos exposure.
  • Cited studies reported that tumor-associated macrophages make up about 25-40% of immune cells in human MPM tumors. The authors noted that studies disagree on whether macrophages predict survival.
  • Cited studies of inherited (germline) BAP1 variants reported a frequency of 7.7% in a cohort of 39 patients (Betti et al.) and 30.7% in a cohort of 52 patients (Pastorino et al.).
  • Pastorino et al., as cited, reported that mesotheliomas in people with BAP1 defects occur more often with no or low asbestos exposure.
  • Bononi et al., as cited, reported that inherited heterozygous mutations in the Bloom syndrome gene (BLM) promote mesothelioma development, with the risk further increased by asbestos exposure.
  • Other cited studies associated copy number changes in CDKN2A and p16 with higher asbestos fiber exposure.
  • Two large genomic studies (Bueno et al. 2016; Hmeljak et al. 2018) found a low mutational burden in MPM. Mansfield et al., as cited, found chromothripsis (chromosome shattering) in 69% of patients in the TCGA MESO cohort.
  • In the PROMISE-meso trial, as cited, 48.9% of patients had less than 1% PD-L1 expression, 28.2% had 1-20%, and 18.5% had more than 20%.
  • The authors stated that early data did not allow a clear conclusion on whether PARP-inhibitor drugs are effective in mesothelioma.
  • The authors stated that none of the proposed microRNA diagnostic markers or signatures is in routine clinical use.
  • In the cited phase III VANTAGE-014 trial, vorinostat showed no improvement in overall survival compared with placebo.
• The authors' conclusion: The authors concluded that targeting the tumor microenvironment with nivolumab (anti-PD1) plus ipilimumab (anti-CTLA-4) had proven the most effective strategy. They also concluded that comprehensive knowledge of MPM biology is crucial for understanding the disease and improving patients' outcomes.
• Limitations the authors state:
  • The authors noted that proposed blood microRNA markers usually lack large validation studies by independent research groups.
  • The authors noted that T-cell studies mostly analyze epithelioid tumors and include few cases of the more aggressive sarcomatoid form.
  • The authors noted that reported PD-L1 positivity rates depend on the study, the cohort and the assay used.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Chemotherapy, Pemetrexed (Alimta), Prognosis, Median Overall Survival, Tumor Suppressor Gene.

Related studies

• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• 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)
• Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma — S. Mitra, M. Lauss, et al. (2020)
• Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma — F. Napoli, A. Listì, et al. (2021)
• Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution — C. Jackaman, D.J. Nelson (2010)
• Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma — A.N. Qualiotto, C.M. Baldavira, et al. (2023)

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