The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy

Our plain-English summary of The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy, by G.J. Chu, N. van Zandwijk, J.E.J. Rasko (Frontiers in Oncology, 2019).

The study

• Authors: G.J. Chu, N. van Zandwijk, J.E.J. Rasko
• Journal: Frontiers in Oncology
• Published: 2019;9:1366
• Type of article: Review
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.

Copyright © 2019 Chu, van Zandwijk and Rasko.

In plain English

This article is a mini review, not a new study. The authors summarized published research on the environment surrounding mesothelioma tumours, mainly malignant pleural mesothelioma, to look for reasons why immunotherapy has worked less well in mesothelioma than in melanoma and non-small cell lung cancer. They described how the inflammatory response to asbestos fibres is thought to contribute to the disease. They then reviewed the surrounding tissue, the chemical signals the tumour releases, low oxygen and competition for nutrients, and the immune cells present. According to the studies reviewed, tumour-associated macrophages made up on average 26%-42% of immune cells in tumours, T-cells 20-42% and granulocytes 6-9%. Many of these cells were reported to suppress immune responses, and T-cells showed markers of exhaustion. The authors noted that T-cell numbers are associated with prognosis but that causation cannot be concluded. They cited a Phase 3 trial in which pembrolizumab was not superior to single-agent chemotherapy in previously treated patients. The authors concluded that the tumour environment may well affect these less positive 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: Mini review of published research (no new data collected)
• Who was studied: No study population of its own. The authors reviewed published research specific to mesothelioma, mainly malignant pleural mesothelioma. This included human tumour tissue, pleural effusions, cell lines, mouse models and clinical trials.
• Exposure: Not an exposure study. The review discusses the inflammatory response to asbestos fibres, including amphibole fibres, as background to how mesothelioma develops. Its main subject is the tumour immune microenvironment and resistance to immunotherapy.
• Main results:
  • In the studies reviewed, tumour-associated macrophages made up on average 26%-42% of the cellular immune infiltrate in mesothelioma, measured by immunohistochemistry.
  • In the studies reviewed, CD3+ T-lymphocytes were the second most common immune cell, making up on average 20-42% of the immune cell infiltrate.
  • In the studies reviewed, the granulocytic infiltrate was less prominent, on average 6-9% of the cellular infiltrate.
  • Cited research reported that CD8+ cytotoxic T-cells in mesothelioma display markers of exhaustion: PD-1, TIM3 and LAG3.
  • The authors noted that T-cell numbers are associated with prognosis but that causation cannot be concluded. Two cited studies linked more CD4+ T-cells in epithelioid mesothelioma with a better prognosis.
  • Cited research reported that stroma-related genes were associated with so-called immune deserts, which are tumour regions with little lymphocyte infiltrate.
  • In a cited trial, PD-L1 expression was associated with a higher objective response rate to nivolumab, but it did not fully predict response.
  • In the cited Phase 3 PROMISE-meso trial, pembrolizumab was not superior to single-agent chemotherapy in previously treated malignant pleural mesothelioma.
  • The authors judged that current evidence does not indicate that natural killer (NK) cells play a key role in the mesothelioma tumour microenvironment.
• The authors' conclusion: The authors concluded that checkpoint inhibition outcomes in mesothelioma have been less positive than in several other solid tumours, and that this may well be affected by the complex structure of the tumour microenvironment. They hoped that a better understanding of it would help find a rationale for more effective therapy combinations.
• Limitations the authors state:
  • The authors acknowledged that the review may not adequately emphasise the significant heterogeneity between patients and within the tumour microenvironment itself.
  • The authors noted that the cited experiments on myeloid-derived suppressor cells used peripheral blood granulocytes rather than tumour-associated cells.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy, Non-Small Cell Lung Cancer, Tumor Microenvironment, Cytokine.

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• 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)
• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma — S. Hiltbrunner, L. Mannarino, et al. (2021)
• Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma — S. Mitra, M. Lauss, et al. (2020)
• Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients — N. Fusco, V. Vaira, et al. (2020)

Browse more research in Frontiers in Oncology, or return to medical research.