Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy
Background Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemo...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| author | Arndt Hartmann Bernd Wullich Markus Eckstein Pamela Strissel Reiner Strick Veronika Weyerer Ralph Wirtz Carolin Pfannstiel Adrian Wullweber Fabienne Lange Philipp Erben Robert Stoehr Simone Bertz Carol Imanuel Geppert Nicole Fuhrich Helge Taubert Sven Wach Johannes Breyer Wolfgang Otto Maximilian Burger Christian Bolenz Bastian Keck Danijel Sikic |
| author_facet | Arndt Hartmann Bernd Wullich Markus Eckstein Pamela Strissel Reiner Strick Veronika Weyerer Ralph Wirtz Carolin Pfannstiel Adrian Wullweber Fabienne Lange Philipp Erben Robert Stoehr Simone Bertz Carol Imanuel Geppert Nicole Fuhrich Helge Taubert Sven Wach Johannes Breyer Wolfgang Otto Maximilian Burger Christian Bolenz Bastian Keck Danijel Sikic |
| author_sort | Arndt Hartmann |
| collection | DOAJ |
| description | Background Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit.Patients and methods Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival.Results The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44–0.74; TCGA: ρ-range: 0.56–0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with ‘inflamed high’ tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort).Conclusion The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy. |
| format | Article |
| id | doaj-art-8c572575ad5b414ebe80d9b210269148 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-8c572575ad5b414ebe80d9b2102691482025-08-20T02:13:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000162Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapyArndt Hartmann0Bernd Wullich1Markus Eckstein2Pamela Strissel3Reiner Strick4Veronika Weyerer5Ralph Wirtz6Carolin Pfannstiel7Adrian Wullweber8Fabienne Lange9Philipp Erben10Robert Stoehr11Simone Bertz12Carol Imanuel Geppert13Nicole Fuhrich14Helge Taubert15Sven Wach16Johannes Breyer17Wolfgang Otto18Maximilian Burger19Christian Bolenz20Bastian Keck21Danijel Sikic224 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany3 Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, GermanyInstitute of Pathology and Comprehensive Cancer Center EMN, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany2 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany2 Laboratory for Molecular Medicine, Department of Gynecology and Obstetrics, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany1 Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany3 STRATIFYER Molecular Pathology, Cologne, Germany1 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany1 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany1 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany4 Department of Urology, Ruprecht-Karls-Universität Heidelberg Medizinische Fakultät Mannheim, Mannheim, Germany3 Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany1 Institute of Pathology, University Hospital Erlangen-Nürnberg, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyInstitute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany1 Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany5 Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany3 Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany6 Department of Urology, Universitätsklinikum Regensburg, Universität Regensburg, Regensburg, Germany6 Department of Urology, Universitätsklinikum Regensburg, Universität Regensburg, Regensburg, GermanyDepartment of Urology, Caritas-Krankenhaus Sankt Josef Regensburg, Regensburg, Germany7 Department of Urology and Pediatric Urology, Universitätsklinikum Ulm, Universität Ulm, Ulm, Germany5 Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, GermanyBackground Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit.Patients and methods Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival.Results The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44–0.74; TCGA: ρ-range: 0.56–0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with ‘inflamed high’ tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort).Conclusion The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.https://jitc.bmj.com/content/8/1/e000162.full |
| spellingShingle | Arndt Hartmann Bernd Wullich Markus Eckstein Pamela Strissel Reiner Strick Veronika Weyerer Ralph Wirtz Carolin Pfannstiel Adrian Wullweber Fabienne Lange Philipp Erben Robert Stoehr Simone Bertz Carol Imanuel Geppert Nicole Fuhrich Helge Taubert Sven Wach Johannes Breyer Wolfgang Otto Maximilian Burger Christian Bolenz Bastian Keck Danijel Sikic Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy Journal for ImmunoTherapy of Cancer |
| title | Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| title_full | Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| title_fullStr | Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| title_full_unstemmed | Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| title_short | Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| title_sort | cytotoxic t cell related gene expression signature predicts improved survival in muscle invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
| url | https://jitc.bmj.com/content/8/1/e000162.full |
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