{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:19:55Z","timestamp":1782271195948,"version":"3.54.5"},"reference-count":27,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,3,29]],"date-time":"2020-03-29T00:00:00Z","timestamp":1585440000000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"KWF\/ZonMW","award":["95104006"],"award-info":[{"award-number":["95104006"]}]},{"name":"Amphera BV"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,2,26]]},"published-print":{"date-parts":[[2020,3]]},"abstract":"\n Background<\/jats:title>\n Malignant pleural mesothelioma (MPM) is a highly lethal malignancy in need for new treatment options. Although immunotherapies have been shown to boost a tumor-specific immune response, not all patients respond and prognostic biomarkers are scarce. In this study, we determined the peripheral blood T cell receptor \u03b2 (TCR\u03b2) chain repertoire of nine MPM patients before and 5\u2009weeks after the start of dendritic cell (DC)-based immunotherapy.<\/jats:p>\n <\/jats:sec>\n \n Materials and methods<\/jats:title>\n We separately profiled PD1+<\/jats:sup> and PD1\u2212<\/jats:sup>CD4+<\/jats:sup> and CD8+<\/jats:sup> T cells, as well as Tregs and analyzed 70 000 TCR\u03b2 sequences per patient.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Strikingly, limited TCR\u03b2 repertoire diversity and high average clone sizes in total CD3+<\/jats:sup> T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCR\u03b2 repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCR\u03b2 clones present in the total CD3+<\/jats:sup> T cell fractions were classified into five categories, based on therapy-associated frequency changes: expanding, decreasing, stable, newly appearing and disappearing clones. Subsequently, the presence of these five groups of clones was analyzed in the individual sorted T cell fractions. DC-therapy primarily induced TCR\u03b2 repertoire changes in the PD1+<\/jats:sup>CD4+<\/jats:sup> and PD1+<\/jats:sup>CD8+<\/jats:sup> T cell fractions. In particular, in the PD1+<\/jats:sup>CD8+<\/jats:sup> T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1\u2212<\/jats:sup> to a PD1+<\/jats:sup> phenotype was significantly more frequent in CD8+<\/jats:sup> T cells than in CD4+<\/jats:sup> T cells. Hereby, the number of expanding PD1+<\/jats:sup>CD8+<\/jats:sup> T cell clones\u2014and not expanding PD1+<\/jats:sup>CD4+<\/jats:sup> T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCR\u03b2 repertoire of total CD3+<\/jats:sup> T cells and on therapy-induced changes, in particular expanding PD1+<\/jats:sup>CD8+<\/jats:sup> T cell clones. Therefore, TCR\u03b2 repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy.<\/jats:p>\n <\/jats:sec>\n \n Trial registration number<\/jats:title>\n \n NCT02395679<\/jats:ext-link>.<\/jats:p>\n <\/jats:sec>","DOI":"10.1136\/jitc-2019-000251","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T05:45:15Z","timestamp":1585633515000},"page":"e000251","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma"],"prefix":"10.1136","volume":"8","clinical-trial-number":[{"clinical-trial-number":"nct02395679","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-935X","authenticated-orcid":false,"given":"Heleen","family":"Vroman","sequence":"first","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Balzaretti","sequence":"additional","affiliation":[{"name":"Clinical Immunology & Rheumatology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"},{"name":"Experimental Immunology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Belderbos","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul L","family":"Klarenbeek","sequence":"additional","affiliation":[{"name":"Clinical Immunology & Rheumatology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"},{"name":"Experimental Immunology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menno","family":"van Nimwegen","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Bezemer","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Cornelissen","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse T G","family":"Niewold","sequence":"additional","affiliation":[{"name":"Laboratory of Genome Analysis, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbera D","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antione H","family":"van Kampen","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G J V","family":"Aerts","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"},{"name":"Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niek","family":"de Vries","sequence":"additional","affiliation":[{"name":"Clinical Immunology & Rheumatology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi W","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,3,30]]},"reference":[{"key":"2025100304284408000_8.1.e000251.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.42"},{"key":"2025100304284408000_8.1.e000251.2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.immuni.2018.03.007","article-title":"Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies","volume":"48","author":"Patel","year":"2018","journal-title":"Immunity"},{"key":"2025100304284408000_8.1.e000251.3","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/S1470-2045(17)30446-1","article-title":"Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (determine): a multicentre, international, randomised, double-blind, placebo-controlled phase 2B trial","volume":"18","author":"Maio","year":"2017","journal-title":"Lancet Oncol"},{"key":"2025100304284408000_8.1.e000251.4","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S1470-2045(17)30169-9","article-title":"Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1B trial","volume":"18","author":"Alley","year":"2017","journal-title":"Lancet Oncol"},{"key":"2025100304284408000_8.1.e000251.5","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.jtho.2018.05.038","article-title":"Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma","volume":"13","author":"Quispel-Janssen","year":"2018","journal-title":"J Thorac Oncol"},{"key":"2025100304284408000_8.1.e000251.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232227"},{"key":"2025100304284408000_8.1.e000251.7","doi-asserted-by":"crossref","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":"2017","journal-title":"Oncoimmunology"},{"key":"2025100304284408000_8.1.e000251.8","doi-asserted-by":"crossref","unstructured":"Minnema-Luiting J , Vroman H , Aerts J , et al . 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T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. 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