Spatial Landscape of Malignant Pleural and Peritoneal Mesothelioma Tumor Immune Microenvironments

Our plain-English summary of Spatial Landscape of Malignant Pleural and Peritoneal Mesothelioma Tumor Immune Microenvironments, by X. Ma, D. Lembersky, E.S. Kim, et al (Cancer Research Communications, 2024).

The study

• Authors: X. Ma, D. Lembersky, E.S. Kim, M.J. Becich, J.R. Testa, T.C. Bruno, H.U. Osmanbeyoglu
• Journal: Cancer Research Communications
• Published: 2024;4(8):2133-2146
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: Immunotherapies have demonstrated limited clinical efficacy in malignant mesothelioma treatment. We conducted multiplex immunofluorescence analyses on tissue microarrays (n = 3) from patients with malignant pleural mesothelioma (MPM, n = 88) and malignant peritoneal mesothelioma (MPeM, n = 25). Our study aimed to elucidate spatial distributions of key immune cell populations and their association with lymphocyte activation gene 3 (LAG3), BRCA1-associated protein 1 (BAP1), neurofibromatosis type 2 (NF2), and methylthioadenosine phosphorylase (MTAP), with MTAP serving as a cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/B) surrogate marker. Additionally, we examined the relationship between the spatial distribution of major immune cell types and prognosis and clinical characteristics of patients with malignant mesothelioma. We observed a higher degree of interaction between immune cells and tumor cells in MPM compared with MPeM. Notably, within MPM tumors, we detected a significantly increased interaction between tumor cells and CD8+ T cells in tumors with low BAP1 expression compared with those with high BAP1 expression. To support the broader research community, we have developed The Human Spatial Atlas of Malignant Mesothelioma, containing hematoxylin and eosin and multiplex immunofluorescence images with corresponding metadata.

Significance: Considering the limited therapeutic options available to patients with malignant mesothelioma, there is substantial translational potential in understanding the correlation between the spatial architecture of the malignant mesothelioma tumor immune microenvironment and tumor biology. Our investigation reveals critical cell-cell interactions that may influence the immune response against malignant mesothelioma tumors, potentially contributing to the differential behaviors observed in MPM and MPeM. These findings represent a valuable resource for the malignant mesothelioma cancer research community.

©2024 The Authors; Published by the American Association for Cancer Research.

In plain English

This laboratory study, which the authors describe as retrospective, examined stored tumor tissue from 115 patients held by the National Mesothelioma Virtual Bank: 88 with malignant pleural mesothelioma (MPM), 25 with malignant peritoneal mesothelioma (MPeM) and 2 with other types. Using multiplex immunofluorescence staining of small tissue cores, the authors mapped immune cells and tumor cells and measured the proteins BAP1, NF2, MTAP and LAG3. Asbestos exposure was confirmed in 33% of patients and unknown in 62%. Median survival from diagnosis was 12 months. Patients with MPeM survived significantly longer than those with MPM. The 6 patients recorded as having no asbestos exposure also survived significantly longer (P = 0.015). Immune cells and tumor cells were in contact more often in MPM than in MPeM. Lower BAP1 levels went with more CD8+ T cells and dendritic cells. In MPM, tumors with low BAP1 showed more contact between tumor cells and CD8+ T cells. The authors listed as limits the small cores, the small sample, the use of only nine markers, and the lack of treatment-response data. They concluded their approach could make tumor immune architecture a new marker. They also built an online image atlas.

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 laboratory study of tumor tissue microarrays using multiplex immunofluorescence staining and spatial image analysis
• Who was studied: 115 patients with malignant mesothelioma (88 pleural, 25 peritoneal, 2 other), one sample per patient, 336 tissue cores in three tissue microarrays from the National Mesothelioma Virtual Bank, prepared at Roswell Park Cancer Institute (53 patients), University of Pennsylvania (30) and University of Pittsburgh (32)
• Exposure: Not an exposure study. Asbestos exposure status was recorded: yes in 38 patients (33%), no in 6 (5.2%), unknown in 71 (62%). Fiber types were not reported. The study measured immune cell types and the proteins BAP1, NF2, MTAP and LAG3 in tumor tissue.
• Main results:
  • Median survival from diagnosis for the whole cohort was 12 months, with an interquartile range of 7 to 24 months
  • Patients with MPeM had significantly longer overall survival than patients with MPM (log-rank P = 0.005)
  • Patients with no asbestos exposure (6 patients) had significantly longer overall survival (P = 0.015)
  • Immune cells and tumor cells were in contact more often in MPM than in MPeM, including CD4+ T cells, CD8+ T cells, macrophages and Tregs (FDR less than 0.1)
  • CD8+ T cells made up 13.81% of cells in MPM and 8.89% in MPeM. Tumor cells made up 39.16% in MPeM and 31.04% in MPM.
  • According to the text, these differences in cell proportions between MPM and MPeM were not statistically significant
  • Patients whose tumors showed higher variety of cell types (higher intratumor heterogeneity) had more favorable overall survival (P = 0.03)
  • In both MPM and MPeM, BAP1 protein levels were negatively correlated with CD8 and CD11c (dendritic cell) marker levels
  • In MPM and MPeM, tumors with low BAP1 had significantly greater infiltration by cytotoxic (CD8+) T cells and dendritic cells
  • Among tumors with low BAP1, contacts between tumor cells and CD8+ T cells were increased in MPM but not in MPeM
  • Patients without asbestos exposure had higher proportions of B cells in their tumors
  • In an exploratory analysis, more CD4+ T cells and more B and CD4+ T cell–enriched stroma (CN3) were linked to better survival in MPeM. CN3 was linked to worse survival in MPM.
  • The authors built a public web portal of the stained tissue images (The Human Spatial Atlas of Malignant Mesothelioma)
• The authors' conclusion: The authors concluded that their study has the potential to establish the spatial architecture of the tumor immune microenvironment as a new marker in malignant mesothelioma
• Limitations the authors state:
  • The small tissue cores may not represent the whole tumor
  • The relatively small sample size limits statistical power and multivariable modeling
  • Only nine markers were used, so specific immune cell subtypes could not be distinguished
  • There were no matching data on response to treatment

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Mesothelioma, Pleural Mesothelioma, BAP1, MTAP, CDKN2A, Prognosis.

Related studies

• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Malignant Peritoneal Mesothelioma: Characterization of the Inflammatory Response in the Tumor Microenvironment — S. Judge, P. Thomas, et al. (2016)
• Molecular Analysis of a Patient With Neurofibromatosis 2 (NF2) and Peritoneal Malignant Mesothelioma — C. Glass, L.M. Sholl, et al. (2020)
• Usefulness of methylthioadenosine phosphorylase and BRCA-associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens — K.B. Berg, A.M. Churg, et al. (2020)
• The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes — F. Torricelli, F. Spada, et al. (2025)
• A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma — Y. Kinoshita, T. Hida, et al. (2018)

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