Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma

Our plain-English summary of Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma, by A.N. Qualiotto, C.M. Baldavira, M. Balancin, et al (Frontiers in Immunology, 2023).

The study

• Authors: A.N. Qualiotto, C.M. Baldavira, M. Balancin, A. Ab'Saber, T. Takagaki, V.L. Capelozzi
• Journal: Frontiers in Immunology
• Published: 2023;14:1268927
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts.

Methods: The discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database.

Results: Most patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients [hazard ratio (HR), 3.42 (1.15-10.16)] with low tumor mesothelin levels [HR, 2.58 (1.09-6.10)] and high PD-L1 and low infiltration of T cells CD4+ [HR, 3.81 (1.58-9.18)]. In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival.

Conclusion: Tumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.

Copyright © 2023 Qualiotto, Baldavira, Balancin, Ab’Saber, Takagaki and Capelozzi.

In plain English

Researchers at the University of São Paulo, Brazil, studied whether levels of the protein mesothelin in mesothelioma tumors were linked to surrounding immune cells, collagen and survival. They analyzed tissue from 82 patients with malignant mesothelioma. The pleura was the primary site in 75.6% of cases. Of the 82 patients, 53.7% had a history of asbestos exposure; no fiber type was reported. During follow-up, 59.8% died. Higher tumor mesothelin was associated with the epithelioid tumor type and with more CD8+ T cells, CD68+ macrophages and collagen type I fibers. In multivariate analysis, risk of death was higher for patients without surgery (hazard ratio 3.42, 95% CI 1.15 to 10.16), with low mesothelin (2.58, 1.09 to 6.10) and with low CD4+ T cells (3.81, 1.58 to 9.18). Asbestos exposure was not significantly associated with risk of death. In 87 tumors from The Cancer Genome Atlas database, low mesothelin and high COL1A1 and COL5A1 gene expression were associated with poorer survival. The authors concluded that mesothelin may be a biomarker for diagnosis and an immunotherapy target. Several numbers in the article are internally inconsistent.

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 study of tumor tissue samples using immunohistochemistry, immunofluorescence and digital image analysis (discovery cohort), plus a computer-based analysis of public gene-expression data from The Cancer Genome Atlas (exploratory cohort)
• Who was studied: 82 patients with malignant mesothelioma whose samples came from three University of São Paulo institutions (InCor, ICESP, HC-FMUSP) in São Paulo, Brazil. The 82 were selected from 246 cases identified. All were reported as stage III/IV. The pleura was the primary site in 62 (75.6%); 20 (24.4%) were extra-pleural. Median age was 60 and 70.7% were male. No study dates are given. A second group of 87 mesothelioma tumors came from The Cancer Genome Atlas (median age 64, 81.6% male).
• Exposure: The main factor studied was mesothelin protein in tumor cells, compared with immune cells (CD4, CD8, CD20, CD68), PD-L1, and collagen and elastin fibers. Asbestos exposure history was recorded: 44 (53.7%) exposed and 38 (46.3%) not exposed. No fiber types, products, jobs or doses are reported.
• Main results:
  • In the 82-patient cohort, the median mesothelin expression was 21.05% positive tumor cells (interquartile range 5.61 to 38.68%). This median was used to divide patients into low and high groups.
  • Low mesothelin expression was associated with tumor necrosis (P = 0.03) and nuclear grade 1 (P = 0.007).
  • High mesothelin expression was found in 46.8% of epithelioid tumors and 0.0% of sarcomatoid tumors (P = 0.003).
  • High tumor mesothelin was significantly associated with a high density of CD8+ T cells (P = 0.01) and CD68+ macrophages (P = 0.008) in the tissue around the tumor.
  • High tumor mesothelin was significantly associated with a high density of collagen type I fibers (P = 0.005). No significant association was found with collagen type V or elastin fibers.
  • In multivariate Cox analysis of the 82-patient cohort, patients who did not have surgery had a higher risk of death than operated patients: hazard ratio 3.42 (1.15 to 10.16), P 0.02.
  • In the multivariate analysis, mesothelin below 21.05 had a higher risk of death than mesothelin of 21.05 or more: hazard ratio 2.58 (1.09 to 6.10), P 0.03.
  • In the multivariate analysis, CD4+ T cells below 44.97 per mm2 had a higher risk of death than 44.97 or more: hazard ratio 3.81 (1.58 to 9.18), P 0.003.
  • In the multivariate table, PD-L1 below 0.35 had a lower risk of death than 0.35 or more: hazard ratio 0.43 (0.19 to 0.94), P 0.03. The text instead gives the PD-L1 median as 0.58%.
  • No asbestos exposure, compared with exposure, was not significantly associated with risk of death. Univariate hazard ratio was 0.70 (0.37 to 1.35), P 0.29; multivariate hazard ratio was 0.70 (0.29 to 1.67), P 0.42.
  • During follow-up, 59.8% of the 82 patients died from disease complications. Survival was 18.4 months (range 0.23 to 46.4); the text calls this the median and Table 1 calls it the mean.
  • In the 87 Cancer Genome Atlas tumors, low mesothelin (P = 0.002), high COL1A1 (P = 0.007) and high COL5A1 (P less than 0.001) gene expression were significantly associated with poorer overall survival.
• The authors' conclusion: The authors concluded that their findings suggest mesothelin has potential as a biomarker for diagnosing malignant pleural mesothelioma and as a target for immunotherapy.

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: Mesothelin, Tumor Microenvironment, Pleural Mesothelioma, PD-L1, Discovery, Immunohistochemistry, Biomarker, Collagen.

Related studies

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• Molecular and Histopathological Characterization of the Tumor Immune Microenvironment in Advanced Stage of Malignant Pleural Mesothelioma — N.S. Patil, L. Righi, et al. (2018)
• Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland — D. Vizcaya, B. Farahmand, et al. (2020)
• 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)
• Characterization of the immune microenvironment in malignant pleural mesothelioma reveals prognostic subgroups of patients — N. Fusco, V. Vaira, et al. (2020)

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