{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T06:53:36Z","timestamp":1777359216373,"version":"3.51.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008376","name":"Helsingin ja Uudenmaan Sairaanhoitopiiri","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003128","name":"Ty\u00f6suojelurahasto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003128","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007247","name":"Svenska Kulturfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007247","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009067","name":"K. Albin Johanssons Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010135","name":"Finska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010116","name":"Medicinska Underst\u00f6dsf\u00f6reningen Liv och H\u00e4lsa","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010116","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008723","name":"Suomen L\u00e4\u00e4ketieteen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008723","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008309","name":"Hengityssairauksien Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008309","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%\u201310% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving \u2265 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that type M2 pro-tumorigenic macrophages (CD163<jats:sup>+<\/jats:sup>pSTAT1<jats:sup>\u2212<\/jats:sup>HLA-DRA1<jats:sup>\u2212<\/jats:sup>) were independently associated with shorter survival, whereas granzyme B<jats:sup>+<\/jats:sup> cells and CD11c<jats:sup>+<\/jats:sup> cells were independently associated with longer survival. CD11c<jats:sup>+<\/jats:sup> cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B\/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.870352","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T07:01:08Z","timestamp":1655708468000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma"],"prefix":"10.3389","volume":"12","author":[{"given":"Hely","family":"Ollila","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikko I.","family":"M\u00e4yr\u00e4np\u00e4\u00e4","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lassi","family":"Paavolainen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juuso","family":"Paajanen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"V\u00e4lim\u00e4ki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Sutinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jari","family":"R\u00e4s\u00e4nen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olli","family":"Kallioniemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjukka","family":"Myll\u00e4rniemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilkka","family":"Ilonen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teijo","family":"Pellinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1080\/0284186X.2018.1532599","article-title":"Malignant Pleural Mesothelioma in Finland: Regional and Gender Variation","volume":"58","author":"Laaksonen","year":"2019","journal-title":"Acta Oncol (Madr)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e3181f1cf2b","article-title":"Malignant Pleural Mesothelioma: A Population-Based Study of Survival","volume":"5","author":"Milano","year":"2010","journal-title":"J Thorac Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/CARCIN\/BGZ004","article-title":"Prognostic Factors of Survival in Patients With Malignant Pleural Mesothelioma: An Analysis of the National Cancer Database","volume":"40","author":"Van Gerwen","year":"2019","journal-title":"Carcinogenesis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/FONC.2021.660039\/BIBTEX","article-title":"Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma","volume":"11","author":"Hiltbrunner","year":"2021","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/JITC-2021-003032","article-title":"Matter of TIME: The Tumor-Immune Microenvironment of Mesothelioma and Implications for Checkpoint Blockade Efficacy","volume":"9","author":"Harber","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1530\u201340","DOI":"10.1016\/S1470-2045(21)00471-X","article-title":"Nivolumab Versus Placebo in Patients With Relapsed Malignant Mesothelioma (CONFIRM): A Multicentre, Double-Blind, Randomised, Phase 3 Trial","author":"Fennell","year":"2021","journal-title":"Lancet Oncol"},{"key":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01519","article-title":"Malignant Pleural Mesothelioma: State-Of-the-Art on Current Therapies and Promises for the Future","volume":"9","author":"Nicolini","year":"2020","journal-title":"Front Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1009285-1\u20139","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":"B10","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.jtcvs.2007.10.026","article-title":"Impact of Tumor-Infiltrating T Cells on Survival in Patients With Malignant Pleural Mesothelioma Anraku Et Al General Thoracic Surgery","volume":"135","author":"Anraku","year":"2008","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e1261241-3\u201310","DOI":"10.1080\/2162402X.2016.1261241","article-title":"Prognostic and Predictive Aspects of the Tumor Immune Microenvironment and Immune Checkpoints in Malignant Pleural Mesothelioma","volume":"6","author":"Marcq","year":"2016","journal-title":"Oncoimmunology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/ANNONC\/MDY086","article-title":"Malignant Pleural Mesothelioma Immune Microenvironment and Checkpoint Expression: Correlation With Clinical-Pathological Features and Intratumor Heterogeneity Over Time","volume":"29","author":"Pasello","year":"2018","journal-title":"Ann Oncol Off J Eur Soc Med Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/J.LUNGCAN.2020.09.026","article-title":"Characterization of the Immune Microenvironment in Malignant Pleural Mesothelioma Reveals Prognostic Subgroups of Patients","volume":"150","author":"Fusco","year":"2020","journal-title":"Lung Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/BJC.2017.269","article-title":"Evaluating the Effect of Immune Cells on the Outcome of Patients With Mesothelioma","volume":"117","author":"Chee","year":"2017","journal-title":"Br J Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-010-0881-6","article-title":"CD8+ Tumor-Infiltrating Lymphocytes Predict Favorable Prognosis in Malignant Pleural Mesothelioma After Resection","volume":"59","author":"Yamada","year":"2010","journal-title":"Cancer Immunol Immunother"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3892\/IJO.2019.4883","article-title":"Role of Evaluating Tumor\u2212Infiltrating Lymphocytes, Programmed Death\u22121 Ligand 1 and Mismatch Repair Proteins Expression in Malignant Mesothelioma","volume":"55","author":"Losi","year":"2019","journal-title":"Int J Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/J.JTHO.2019.03.029","article-title":"Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma","volume":"14","author":"Salaroglio","year":"2019","journal-title":"J Thorac Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e106742-1\u20139","DOI":"10.1371\/journal.pone.0106742","article-title":"Ratio of Intratumoral Macrophage Phenotypes Is a Prognostic Factor in Epithelioid Malignant Pleural Mesothelioma","volume":"9","author":"Cornelissen","year":"2014","journal-title":"PloS One"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.26143","article-title":"Circulating and Tumor-Infiltrating Myeloid Cells Predict Survival in Human Pleural Mesothelioma","volume":"117","author":"Burt","year":"2011","journal-title":"Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.218","article-title":"High Tumor Cell Platelet-Derived Growth Factor Receptor Beta Expression Is Associated With Shorter Survival in Malignant Pleural Epithelioid Mesothelioma","volume":"7","author":"Ollila","year":"2021","journal-title":"J Pathol Clin Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/J.CELS.2020.04.003","article-title":"Nucleaizer: A Parameter-Free Deep Learning Framework for Nucleus Segmentation Using Image Style Transfer","volume":"10","author":"Hollandi","year":"2020","journal-title":"Cell Syst"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/AJCP\/AQAB054","article-title":"Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis","volume":"156","author":"Schulte","year":"2021","journal-title":"Am J Clin Pathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/J.JTHO.2019.08.2506","article-title":"EURACAN\/IASLC Proposals for Updating the Histologic Classification of Pleural Mesothelioma: Towards a More Multidisciplinary Approach","volume":"15","author":"Nicholson","year":"2020","journal-title":"J Thorac Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-021-00895-7","article-title":"Pleural Mesothelioma Classification \u2013 Update and Challenges","volume":"35","author":"Dacic","year":"2022","journal-title":"Mod Pathol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1146\/ANNUREV-IMMUNOL-061020-053707","article-title":"Dendritic Cells Revisited","volume":"39","author":"Cabeza-Cabrerizo","year":"2021","journal-title":"Annu Rev Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMRA1912719","article-title":"Perspectives on the Treatment of Malignant Pleural Mesothelioma","volume":"385","author":"Janes","year":"2021","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/J.JTHO.2016.06.022","article-title":"Pleural Effusions From Patients With Mesothelioma Induce Recruitment of Monocytes and Their Differentiation Into M2 Macrophages","volume":"11","author":"Ch\u00e9n\u00e9","year":"2016","journal-title":"J Thorac Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/J.LUNGCAN.2015.03.013","article-title":"Intratumoral Macrophage Phenotype and CD8+ T Lymphocytes as Potential Tools to Predict Local Tumor Outgrowth at the Intervention Site in Malignant Pleural Mesothelioma","volume":"88","author":"Cornelissen","year":"2015","journal-title":"Lung Cancer"},{"key":"B29","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/J.CELL.2010.03.014","article-title":"Macrophage Diversity Enhances Tumor Progression and Metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2014.00603","article-title":"Th1\/Th2 Paradigm Extended: Macrophage Polarization as an Unappreciated Pathogen-Driven Escape Mechanism","volume":"5","author":"Muraille","year":"2014","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/J.1399-0039.2007.00869.X","article-title":"Th2-Mediated Anti-Tumour Immunity: Friend or Foe","volume":"70","author":"Ellyard","year":"2007","journal-title":"Tissue Antigens"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/FIMMU.2019.00168\/BIBTEX","article-title":"Cold Tumors: A Therapeutic Challenge for Immunotherapy","volume":"10","author":"Bonaventura","year":"2019","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/J.MOLIMM.2007.03.024","article-title":"Human Mast Cells Produce and Release the Cytotoxic Lymphocyte Associated Protease Granzyme B Upon Activation","volume":"44","author":"Strik","year":"2007","journal-title":"Mol Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/EJI.201343711","article-title":"Human Plasma Cells Express Granzyme B","volume":"44","author":"Xu","year":"2014","journal-title":"Eur J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/J.MOLIMM.2007.09.033","article-title":"Expression of Granzyme B in Peripheral Blood Polymorphonuclear Neutrophils (PMN), Myeloid Cell Lines and in PMN Derived From Haemotopoietic Stem Cells In Vitro","volume":"45","author":"Wagner","year":"2008","journal-title":"Mol Immunol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"103040","DOI":"10.1016\/J.EBIOM.2020.103040","article-title":"Efficacy of Nivolumab and Ipilimumab in Patients With Malignant Pleural Mesothelioma is Related to a Subtype of Effector Memory Cytotoxic T Cells: Translational Evidence From Two Clinical Trials","volume":"62","author":"Mankor","year":"2020","journal-title":"EBioMedicine"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/JIMMUNOL.1403134","article-title":"Tumor-Infiltrating Dendritic Cells in Cancer Pathogenesis","volume":"194","author":"Tran Janco","year":"2015","journal-title":"J Immunol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.870352\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T07:01:12Z","timestamp":1655708472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.870352\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":37,"alternative-id":["10.3389\/fonc.2022.870352"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.870352","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]},"article-number":"870352"}}