Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy

Our plain-English summary of Matter of TIME: the tumor-immune microenvironment of mesothelioma and implications for checkpoint blockade efficacy, by J. Harber, T. Kamata, C. Pritchard, et al (Journal for Immunotherapy of Cancer, 2021).

The study

• Authors: J. Harber, T. Kamata, C. Pritchard, D. Fennell
• Journal: Journal for Immunotherapy of Cancer
• Published: 2021;9(9)
• Type of article: Review
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an incurable cancer with a dismal prognosis and few effective treatment options. Nonetheless, recent positive phase III trial results for immune checkpoint blockade (ICB) in MPM herald a new dawn in the fight to advance effective treatments for this cancer. Tumor mutation burden (TMB) has been widely reported to predict ICB in other cancers, but MPM is considered a low-TMB tumor. Similarly, tumor programmed death-ligand 1 (PD-L1) expression has not been proven predictive in phase III clinical trials in MPM. Consequently, the precise mechanisms that determine response to immunotherapy in this cancer remain unknown. The present review therefore aimed to synthesize our current understanding of the tumor immune microenvironment in MPM and reflects on how specific cellular features might impact immunotherapy responses or lead to resistance. This approach will inform stratified approaches to therapy and advance immunotherapy combinations in MPM to improve clinical outcomes further.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

In plain English

This article was a review, not a new study. The authors set out to bring together published research on the immune environment inside malignant pleural mesothelioma (MPM) and to consider how it might affect responses to immune checkpoint blockade drugs. The article describes MPM as causally associated with exposure to asbestos fibers. The review drew on studies in patients, mouse models and cell lines. It reported that, in the studies it cited, cytotoxic T cells typically made up about 5% to 15% of the immune cells in MPM, while tumor-associated macrophages were the predominant immune cell type. Tumor PD-L1 positivity was reported to vary between 20% and 80%, averaging about 40%. The authors stated that recent phase III trials show PD-L1 cannot be considered predictive in MPM at present. They also cited their own group's earlier finding of HLA loss of heterozygosity in 23% of patients with MPM undergoing surgery. The authors concluded that MPM tumors are rarely immunologically 'cold' and may be amenable to treatments that enhance their immunogenicity. They noted that differences between human and mouse immunology complicate the evidence.

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: Narrative review of published research; no new data were collected
• Who was studied: Published studies of malignant pleural mesothelioma, including studies in patients, mouse models and cell lines. The review focused on cytotoxic T cells, tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells and tumor-intrinsic factors. Other immune components were outside its scope.
• Exposure: Not an asbestos exposure study. The subject was the tumor immune microenvironment and immune checkpoint blockade therapy. Asbestos is mentioned only as background, as the cause of MPM; no fiber types are specified.
• Main results:
  • In the studies the review cited, cytotoxic T cells (CD8+ cells) typically represented approximately 5% to 15% of the total immune infiltrate in MPM.
  • The review reported that tumor-associated macrophages are the predominant immune (leukocyte) population in MPM tumors.
  • The review reported that tumor PD-L1 positivity in MPM varies between 20% and 80% overall, averaging approximately 40%.
  • The authors cited their own group's earlier study, which found HLA loss of heterozygosity in 23% of patients with MPM undergoing surgery.
  • The review stated that the evidence accumulated so far indicates that MPMs are rarely 'cold', are commonly 'altered', and are less frequently 'hot' in their immune makeup.
• The authors' conclusion: The authors concluded that the immune environments of MPM tumors are rarely cold and may therefore be amenable to therapeutic interventions that enhance their immunogenicity.
• Limitations the authors state:
  • The authors stated that the roles of other components of the tumor immune microenvironment were beyond the scope of the review.
  • The authors noted that differences between human and mouse immunology make it harder to classify macrophage populations.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, PD-L1, Clinical Trial, Immunotherapy.

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