T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma
Background 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 periphe...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000251.full |
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| author | Niek de Vries Joachim G J V Aerts Paul L Klarenbeek Heleen Vroman Giulia Balzaretti Robert A Belderbos Menno van Nimwegen Koen Bezemer Robin Cornelissen Ilse T G Niewold Barbera D van Schaik Antione H van Kampen Rudi W Hendriks |
| author_facet | Niek de Vries Joachim G J V Aerts Paul L Klarenbeek Heleen Vroman Giulia Balzaretti Robert A Belderbos Menno van Nimwegen Koen Bezemer Robin Cornelissen Ilse T G Niewold Barbera D van Schaik Antione H van Kampen Rudi W Hendriks |
| author_sort | Niek de Vries |
| collection | DOAJ |
| description | Background 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 β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy.Materials and methods We separately profiled PD1+ and PD1−CD4+ and CD8+ T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient.Results Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3+ T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3+ 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 TCRβ repertoire changes in the PD1+CD4+ and PD1+CD8+ T cell fractions. In particular, in the PD1+CD8+ T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1− to a PD1+ phenotype was significantly more frequent in CD8+ T cells than in CD4+ T cells. Hereby, the number of expanding PD1+CD8+ T cell clones—and not expanding PD1+CD4+ T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume.Conclusion We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3+ T cells and on therapy-induced changes, in particular expanding PD1+CD8+ T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy.Trial registration number NCT02395679. |
| format | Article |
| id | doaj-art-5e1fbd76234f42c6be909998facb7a08 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5e1fbd76234f42c6be909998facb7a082024-11-08T16:40:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000251T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesotheliomaNiek de Vries0Joachim G J V Aerts1Paul L Klarenbeek2Heleen Vroman3Giulia Balzaretti4Robert A Belderbos5Menno van Nimwegen6Koen Bezemer7Robin Cornelissen8Ilse T G Niewold9Barbera D van Schaik10Antione H van Kampen11Rudi W Hendriks122 Amsterdam Rheumatology and Immunology Center, Academic Medical Center, Amsterdam, The NetherlandsDepartment of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands2 Amsterdam Rheumatology and Immunology Center, Academic Medical Center, Amsterdam, The Netherlands1 Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands4 Experimental Immunology, Amsterdam UMC - Locatie AMC, Amsterdam, The NetherlandsPulmonary Medicine, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands1 Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands1 Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The NetherlandsPulmonary Medicine, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands5 Laboratory of Genome Analysis, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands6 Clinical Epidemiology, Amsterdam UMC - Locatie AMC, Amsterdam, The Netherlands6 Clinical Epidemiology, Amsterdam UMC - Locatie AMC, Amsterdam, The NetherlandsDepartment of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, the NetherlandsBackground 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 β (TCRβ) chain repertoire of nine MPM patients before and 5 weeks after the start of dendritic cell (DC)-based immunotherapy.Materials and methods We separately profiled PD1+ and PD1−CD4+ and CD8+ T cells, as well as Tregs and analyzed 70 000 TCRβ sequences per patient.Results Strikingly, limited TCRβ repertoire diversity and high average clone sizes in total CD3+ T cells before the start of immunotherapy were associated with a better clinical response. To explore the differences in TCRβ repertoire prior-DC-therapy and post-DC-therapy, for each patient the TCRβ clones present in the total CD3+ 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 TCRβ repertoire changes in the PD1+CD4+ and PD1+CD8+ T cell fractions. In particular, in the PD1+CD8+ T cell subpopulation we found high frequencies of expanding, decreasing and newly appearing clones. Conversion from a PD1− to a PD1+ phenotype was significantly more frequent in CD8+ T cells than in CD4+ T cells. Hereby, the number of expanding PD1+CD8+ T cell clones—and not expanding PD1+CD4+ T cell clones following immunotherapy positively correlated with overall survival, progression-free survival and reduction of tumor volume.Conclusion We conclude that the clinical response to DC-mediated immunotherapy is dependent on both the pre-existing TCRβ repertoire of total CD3+ T cells and on therapy-induced changes, in particular expanding PD1+CD8+ T cell clones. Therefore, TCRβ repertoire profiling in sorted T cell subsets could serve as predictive biomarker for the selection of MPM patients that benefit from immunotherapy.Trial registration number NCT02395679.https://jitc.bmj.com/content/8/1/e000251.full |
| spellingShingle | Niek de Vries Joachim G J V Aerts Paul L Klarenbeek Heleen Vroman Giulia Balzaretti Robert A Belderbos Menno van Nimwegen Koen Bezemer Robin Cornelissen Ilse T G Niewold Barbera D van Schaik Antione H van Kampen Rudi W Hendriks T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma Journal for ImmunoTherapy of Cancer |
| title | T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| title_full | T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| title_fullStr | T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| title_full_unstemmed | T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| title_short | T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| title_sort | t cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in mesothelioma |
| url | https://jitc.bmj.com/content/8/1/e000251.full |
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