{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:00Z","timestamp":1787028480241,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T00:00:00Z","timestamp":1653091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Buzzi Unicem Onlus"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (&gt;36 months) or short (&lt;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.<\/jats:p>","DOI":"10.3390\/ijms23105786","type":"journal-article","created":{"date-parts":[[2022,5,21]],"date-time":"2022-05-21T09:18:08Z","timestamp":1653124688000},"page":"5786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-4228","authenticated-orcid":false,"given":"Laura","family":"Mannarino","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Laboratory of Cancer Pharmacology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Paracchini","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Laboratory of Cancer Pharmacology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-3108","authenticated-orcid":false,"given":"Federica","family":"Pezzuto","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5921-4634","authenticated-orcid":false,"given":"Gheorghe Emilian","family":"Olteanu","sequence":"additional","affiliation":[{"name":"Laboratorul de Anatomie Patologic\u0103, Spitalul Clinic de Boli Infec\u021bioase \u0219i Pneumoftiziologie Victor Babe\u0219, 300223 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Moracci","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Vedovelli","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova Medical School, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4806-7904","authenticated-orcid":false,"given":"Irene","family":"De Simone","sequence":"additional","affiliation":[{"name":"Department of 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Emanuele, 20072 Milan, Italy"},{"name":"Laboratory of Cancer Pharmacology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-1445","authenticated-orcid":false,"given":"Alessia","family":"Inglesi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Callari","sequence":"additional","affiliation":[{"name":"Michelangelo Foundation, 20121 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4274-8792","authenticated-orcid":false,"given":"Serena","family":"Penpa","sequence":"additional","affiliation":[{"name":"Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), Infrastruttura Ricerca Formazione Innovazione (IRFI), Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Libener","sequence":"additional","affiliation":[{"name":"Dipartimento Attivit\u00e0 Integrate Ricerca e Innovazione (DAIRI), Infrastruttura Ricerca Formazione Innovazione (IRFI), Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9862-7340","authenticated-orcid":false,"given":"Sara","family":"Delfanti","sequence":"additional","affiliation":[{"name":"Mesothelioma Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Mesothelioma Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Muzio","sequence":"additional","affiliation":[{"name":"SC Oncologia, Ospedale Santo Spirito, 15033 Casale Monferrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Andrea","family":"Zucali","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Department of Oncology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Allavena","sequence":"additional","affiliation":[{"name":"Department Immunology, IRCCS Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Luca","family":"Ceresoli","sequence":"additional","affiliation":[{"name":"Department of Medical 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Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/s43018-021-00232-6","article-title":"Mature Tertiary Lymphoid Structures Predict Immune Checkpoint Inhibitor Efficacy in Solid Tumors Independently of PD-L1 Expression","volume":"2","author":"Vanhersecke","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1136\/jclinpath-2015-203089","article-title":"Tertiary Lymphoid Structures: Prognostic Significance and Relationship with Tumour-Infiltrating Lymphocytes in Triple-Negative Breast Cancer","volume":"69","author":"Lee","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary Lymphoid Structures in the Era of Cancer Immunotherapy","volume":"19","author":"Petitprez","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41586-019-1906-8","article-title":"B Cells Are Associated with Survival and Immunotherapy Response in Sarcoma","volume":"577","author":"Petitprez","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1158\/1078-0432.CCR-13-2590","article-title":"Occurrence of Tertiary Lymphoid Tissue Is Associated with T-Cell Infiltration and Predicts Better Prognosis in Early-Stage Colorectal Cancers","volume":"20","author":"Bergomas","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eabf9419","DOI":"10.1126\/science.abf9419","article-title":"Tertiary Lymphoid Structures in Cancer","volume":"375","author":"Schumacher","year":"2022","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1007\/s00268-017-4424-6","article-title":"A Nomogram to Predict Prognosis in Malignant Pleural Mesothelioma","volume":"42","author":"Wang","year":"2018","journal-title":"World J. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"838","DOI":"10.3892\/or.2020.7669","article-title":"Connective Tissue Growth Factor Produced by Cancer-Associated Fibroblasts Correlates with Poor Prognosis in Epithelioid Malignant Pleural Mesothelioma","volume":"44","author":"Ohara","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ebiom.2019.09.003","article-title":"Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions","volume":"48","author":"Alcala","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-Line Nivolumab plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma (CheckMate 743): A Multicentre, Randomised, Open-Label, Phase 3 Trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13073-019-0638-6","article-title":"Molecular and Pharmacological Modulators of the Tumor Immune Contexture Revealed by Deconvolution of RNA-Seq Data","volume":"11","author":"Finotello","year":"2019","journal-title":"Genome Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1038\/cmi.2017.35","article-title":"B Cell Regulation in Cancer and Anti-Tumor Immunity","volume":"14","author":"Sarvaria","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, C., Lee, H., Pal, S., Jove, V., Deng, J., Zhang, W., Hoon, D.S.B., Wakabayashi, M., Forman, S., and Yu, H. (2013). B Cells Promote Tumor Progression via STAT3 Regulated-Angiogenesis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064159"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S92","DOI":"10.21037\/tlcr.2019.11.12","article-title":"Chromosomal Rearrangements and Their Neoantigenic Potential in Mesothelioma","volume":"9","author":"Mansfield","year":"2020","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"660039","DOI":"10.3389\/fonc.2021.660039","article-title":"Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma","volume":"11","author":"Hiltbrunner","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_18","first-page":"407","article-title":"Tertiary Lymphoid Structures in Cancers: Prognostic Value, Regulation, and Manipulation for Therapeutic Intervention","volume":"7","author":"Lawand","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1007\/s00428-021-03099-1","article-title":"Tertiary Lymphoid Structures in Epithelioid Malignant Peritoneal Mesothelioma Are Associated with Neoadjuvant Chemotherapy, but Not with Prognosis","volume":"479","author":"Benzerdjeb","year":"2021","journal-title":"Virchows Arch."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1009285","DOI":"10.1080\/2162402X.2015.1009285","article-title":"The Tumoral and Stromal Immune Microenvironment in Malignant Pleural Mesothelioma: A Comprehensive Analysis Reveals Prognostic Immune Markers","volume":"4","author":"Ujiie","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/S0140-6736(15)01238-6","article-title":"Bevacizumab for Newly Diagnosed Pleural Mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A Randomised, Controlled, Open-Label, Phase 3 Trial","volume":"387","author":"Zalcman","year":"2016","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1016\/S1470-2045(21)00404-6","article-title":"Gemcitabine with or without Ramucirumab as Second-Line Treatment for Malignant Pleural Mesothelioma (RAMES): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial","volume":"22","author":"Pinto","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_23","unstructured":"(2020, October 20). Babraham Bioinformatics-FastQC A Quality Control tool for High Throughput Sequence Data. Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","article-title":"MultiQC: Summarize Analysis Results for Multiple Tools and Samples in a Single Report","volume":"32","author":"Ewels","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_25","unstructured":"(2020, October 21). Contents\u2014Bcbio-Nextgen 1.2.4 Documentation. Available online: https:\/\/bcbio-nextgen.readthedocs.io\/en\/latest\/."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-Based Genome Alignment and Genotyping with HISAT2 and HISAT-Genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.12688\/f1000research.12093.2","article-title":"BcbioRNASeq: R Package for Bcbio RNA-Seq Analysis","volume":"6","author":"Steinbaugh","year":"2018","journal-title":"F1000Research"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nmeth.4197","article-title":"Salmon Provides Fast and Bias-Aware Quantification of Transcript Expression","volume":"14","author":"Patro","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential Analyses for RNA-Seq: Transcript-Level Estimates Improve Gene-Level Inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Research"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene Set Enrichment Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression Profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","first-page":"D498","article-title":"The Reactome Pathway Knowledgebase","volume":"48","author":"Jassal","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_33","first-page":"100141","article-title":"ClusterProfiler 4.0: A Universal Enrichment Tool for Interpreting Omics Data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"653497","DOI":"10.3389\/fonc.2021.653497","article-title":"P14\/ARF-Positive Malignant Pleural Mesothelioma: A Phenotype with Distinct Immune Microenvironment","volume":"11","author":"Pezzuto","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.jtho.2021.12.014","article-title":"The 2021 WHO Classification of Tumors of the Pleura: Advances Since the 2015 Classification","volume":"17","author":"Sauter","year":"2022","journal-title":"J. Thorac. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5786\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:16:10Z","timestamp":1760138170000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5786"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,21]]},"references-count":35,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23105786"],"URL":"https:\/\/doi.org\/10.3390\/ijms23105786","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,21]]}}}