Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study

Our plain-English summary of Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study, by L. Mannarino, L. Paracchini, F. Pezzuto, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: L. Mannarino, L. Paracchini, F. Pezzuto, G.E. Olteanu, L. Moracci, L. Vedovelli, I. De Simone, C. Bosetti, M. Lupi, R. Amodeo, A. Inglesi, M. Callari, S. Penpa, R. Libener, S. Delfanti, A. De Angelis, A. Muzio, P.A. Zucali, P. Allavena, G.L. Ceresoli, S. Marchini, F. Calabrese, M. D'Incalci, F. Grosso
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(10)
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.

In plain English

This retrospective analysis from the MATCH study examined tumors from 129 pleural mesothelioma patients who had not had chemotherapy, from seven Italian hospitals (2009 to 2019). Pathologists classified 99 tumors as epithelioid and 30 as non-epithelioid; 45 epithelioid patients survived over 36 months and 54 under 12 months. Gene activity, measured in 69 samples, differed between epithelioid and non-epithelioid tumors but not significantly between long and short epithelioid survivors. Gene-based estimates suggested more B cells (a type of white blood cell) in long survivors and more neutrophils and M2 macrophages in short survivors. Tissue staining for the B-cell marker CD20 scored higher in long than in short survivors (p = 0.025). These estimates sorted epithelioid tumors into two groups. Tertiary lymphoid structures (organized immune-cell clusters) appeared in 83% of 12 reviewed Group B samples, which the authors linked to long survivors, and in 37% of 24 Group A samples. The article did not report or analyze asbestos exposure. The authors concluded that B lymphocytes could influence disease behavior. They noted the study was retrospective with relatively few cases.

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 multicenter cohort study comparing tumor tissue (microscopic review, immunostaining and RNA sequencing) between long and short survivors
• Who was studied: 186 pleural mesothelioma patients were initially selected from seven Italian hospitals (2009 to 2019), and 129 chemonaive patients made up the final cohort. These were 32 women and 97 men, with a median age at diagnosis of 77 years (range 34 to 97). Of the 129 tumors, 99 were epithelioid: 45 from long survivors (more than 36 months) and 54 from short survivors (less than 12 months). The other 30 were non-epithelioid (sarcomatoid or biphasic). RNA sequencing was done on 69 samples.
• Exposure: The article does not report or analyze asbestos exposure. It examined the immune environment of the tumors: B and T lymphocytes, tertiary lymphoid structures, and immune-cell estimates from gene activity. No fiber types, jobs or doses are reported.
• Main results:
  • Comparing epithelioid with non-epithelioid tumors, 817 differentially expressed genes were found. They were mainly involved in immune-regulatory processes and were preferentially activated in the non-epithelioid subtype.
  • Among epithelioid tumors, long and short survivors showed no significant differences in transcriptional features.
  • In the computer-based (quanTIseq) estimate of immune cells, long-survivor epithelioid samples showed overexpression of B cells. Short-survivor samples had a prevalence of neutrophils and M2 macrophages.
  • Immunostaining scores for B (CD20+) cells were higher in long-survivor than in short-survivor epithelioid tumors (p = 0.025).
  • In multivariate analysis, the authors reported that the prevalence of B (CD20+) lymphocytes in long survivors was confirmed: log odds ratio = −0.06; 95% confidence interval −0.12 to −0.001; p = 0.039.
  • Epithelioid tumors were grouped into two clusters (Group A and Group B) by their gene-based immune-cell estimates. Samples were then selected for microscopic review: 24 from Group A and 12 from Group B. Tertiary lymphoid structure formation was seen in 83% of Group B (the B-cell-rich cluster, which the authors describe as epithelioid long survivors) and in 37% of Group A. These are percentages within these selected clusters, not rates for all long versus all short survivors.
• The authors' conclusion: The authors concluded that B (CD20+) lymphocytes could influence the behavior of the disease, and that this suggests a possible path for B-cell-based immunotherapy research. They said larger studies, mechanistic studies and prospective studies are needed.
• Limitations the authors state:
  • The study is retrospective.
  • The number of cases is relatively low.
  • Immune-cell typing by staining was possible for only a few immune-environment markers.

Topics

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

Medical terms in this study, explained in our Lexicon: Epithelioid, Pleural Mesothelioma, Non-epithelioid, Biomarker, Tumor-Infiltrating Lymphocytes.

Related studies

• Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis — N. Benzerdjeb, P. Dartigues, et al. (2021)
• Anti-mesothelin immunotoxin induces mesothelioma eradication, anti-tumor immunity, and the development of tertiary lymphoid structures — W. Liu, C.H. Tai, et al. (2022)
• Multiplexed single-cell and spatial profiling reveal B cells and tertiary lymphoid structures as prognostic indicators in pleural mesothelioma — A. Rigutto, N.G. Núñez, et al. (2026)
• Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations — L. Mannarino, F. Mirimao, et al. (2022)
• EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors — H. Kothmaier, F. Quehenberger, et al. (2008)
• Radiation-induced mesothelioma among long-term solid cancer survivors: a longitudinal analysis of SEER database — A. Farioli, M. Ottone, et al. (2016)

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