The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes

Our plain-English summary of The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes, by F. Torricelli, F. Spada, C. Bishop, et al (Journal of Translational Medicine, 2025).

The study

• Authors: F. Torricelli, F. Spada, C. Bishop, K. Todd, D. Nonaka, N. Petrov, M.T. Barberio, A.G. Ramsay, R. Ellis, A. Ciarrocchi, B. Apollonio, A. Billè
• Journal: Journal of Translational Medicine
• Published: 2025;23(1):208
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with limited therapeutic options. To improve patients management and treatment, more precise stratification strategies are needed. This study aimed to characterize the phenogenomic landscapes of MPM and to understand their influence on patients clinical outcomes.

Methods: We conducted a phenogenomic analysis on 22 MPM patients using two high throughput approaches: imaging mass cytometry (IMC) with whole exome sequencing (WES). Resulting profiles were addressed for their clinical relevance to predict patients prognosis.

Results: IMC revealed a highly heterogeneous tumor microenvironment (TME) with distinct tumor cell subpopulations. Notably, we identified a novel sarcomatoid-like cellular cluster associated with poor prognosis. The TME was also infiltrated with immune cells including macrophages and CD4+ T lymphocytes, that were more abundant in patients with favorable clinical outcomes. WES identified a complex genomic landscape with limited prognostic value for individual genetic alterations. However, tumor mutational burden (TMB) emerged as a potential predictive biomarker, inversely correlating with immune cell infiltration, particularly macrophages and CD4+ T lymphocytes.

Conclusions: Our findings underscore the intricate interplay between the tumor genome, TME composition, and clinical outcomes in MPM. These data support the potential of integrating genomic and TME profiling to develop more precise patient stratification strategies and potentially optimize therapeutic approaches, including immunotherapy.

© 2025. The Author(s).

In plain English

This study examined tumor tissue from 22 patients with pleural mesothelioma treated at King's College Hospital, London, between November 2015 and October 2019, and followed until December 2022. Eighteen of the 22 had previous asbestos exposure. The article gives no fiber types, jobs or doses. Nineteen tumors were epithelioid and 3 biphasic, and 21 patients had chemotherapy plus surgery. The authors used imaging mass cytometry to map the types of cells in the tissue. For 16 patients they also used whole exome sequencing to find tumor mutations. Median overall survival was 29.1 months. A sarcomatoid-like group of tumor cells was significantly associated with shorter survival. Macrophages and CD4+ T lymphocytes were associated with longer survival. BAP1 was mutated in 6 of 16 patients. Patients with low tumor mutational burden (7 patients) had a median survival of 32 months, compared with 8 months for those with high burden (9 patients). The authors concluded that mutational burden may influence the tumor's surrounding tissue and patient outcomes. They noted the small cohort, the absence of sarcomatoid cases, and that no patients received immunotherapy.

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: Retrospective consecutive case series, analyzed by imaging mass cytometry and whole exome sequencing, with survival compared across groups
• Who was studied: 22 patients with biopsy-proven pleural mesothelioma from King's College Hospital, London, November 2015 to October 2019, followed until December 2022. 17 were male and 5 female, with a median age of 72.5 years. 19 were epithelioid and 3 biphasic. 21 had chemotherapy plus pleurectomy decortication and 1 had chemotherapy only. Whole exome sequencing was done for 16 patients.
• Exposure: 18 of 22 patients had previous asbestos exposure. Fiber types, jobs and doses are not reported. The study examined tumor tissue features, not exposure.
• Main results:
  • Median overall survival for the 22 patients was 29.1 months.
  • Among tumor cell groups, a higher frequency of the sarcomatoid-like cluster c6 was significantly associated with shorter survival (short vs long survival defined by a 24-month cut-off).
  • The pericyte cluster c17 was described by the authors as an independent predictor of shorter survival.
  • Immune clusters c9 (macrophages) and c10 (CD4+ T lymphocytes) were associated with longer survival.
  • No association was found between the abundance of Ki67+ tumor cells and survival.
  • In the 16 sequenced patients, BAP1 was mutated in 6/16 (37.5%), NF2 and MT-ND5 each in 4/16 (25%), and TTN in 3/16 (18.8%).
  • No correlation was found between BAP1 or NF2 mutations and prognosis. Patients with MT-ND5 alterations showed a trend towards improved overall survival.
  • Tumor mutational burden in the 16 patients had a median of 2.7, with a range of 1.5 to 5.3 mutations per Mb.
  • Low tumor mutational burden (7 patients) was associated with better overall survival than high burden (9 patients): median overall survival 32 months vs 8 months, p = 0.00091.
  • Tumor mutational burden was inversely correlated with immune cell infiltration.
  • Patients with high macrophage or CD4+ infiltration and low tumor mutational burden had better prognosis than those with low immune infiltration and high burden.
• The authors' conclusion: The authors concluded that tumor mutational burden, although low in mesothelioma compared with other solid tumors, may influence the composition of the tumor microenvironment and, in turn, disease progression and patient outcomes.
• Limitations the authors state:
  • Small patient cohort
  • Patients were mostly epithelioid, with no sarcomatoid cases
  • Patients received surgery and conventional chemotherapy. Immunotherapy-treated patients still need to be studied.
  • The limited number of markers restricted characterization of the tissue, and the panel could not distinguish pro-tumoral from anti-tumoral macrophages.
  • Imaging mass cytometry is not easily scalable to larger cohorts

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Microenvironment, Prognosis, Sarcomatoid, Macrophage, Tumor Mutational Burden (TMB), Biomarker, Immunotherapy.

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