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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doaj-8c572575ad5b414ebe80d9b2102691482021-07-19T12:01:46ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-06-018110.1136/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 StrisselReiner Strick3Veronika WeyererRalph WirtzCarolin PfannstielAdrian WullweberFabienne LangePhilipp ErbenRobert Stoehr4Simone Bertz5Carol Imanuel GeppertNicole FuhrichHelge TaubertSven Wach6Johannes BreyerWolfgang Otto7Christian BolenzBastian Keck8Danijel Sikic9Comprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, Germany1Department of Urology, University Hospital Erlangen, Erlangen, GermanyComprehensive Cancer Center Erlangen-EMN, Erlangen, Bayern, GermanyUniversity-Clinic Erlangen, Department of Obstetrics and Gynecology, Erlangen, GermanyDepartment of Urology, University of Regensburg, 93053 Regensburg, GermanyRegensburg University Medical Center, Department of Pathology, Franz-Josef-Strauss-Allee 11, Regensburg, 93053, GermanyDepartment of Genetics, Nikolaus-Fiebiger Centre of Molecular Medicine, University of Erlangen–Nuremberg, Erlangen, Germany5Department of Proteomics, Helmholtz Centre for Environmental Research, Leipzig, Germany1Department of Urology, University Hospital Erlangen, Erlangen, Germany1Department of Urology, University Hospital Erlangen, 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 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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 Christian Bolenz Bastian Keck Danijel Sikic |
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 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 |
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 Christian Bolenz Bastian Keck Danijel Sikic |
author_sort |
Arndt Hartmann |
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_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_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_sort |
cytotoxic t-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2020-06-01 |
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. |
url |
https://jitc.bmj.com/content/8/1/e000162.full |
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