Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy

Medientyp: E-Artikel
Titel: Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy
Beteiligte: Eckstein, Markus; Strissel, Pamela; Strick, Reiner; Weyerer, Veronika; Wirtz, Ralph; Pfannstiel, Carolin; Wullweber, Adrian; Lange, Fabienne; Erben, Philipp; Stoehr, Robert; Bertz, Simone; Geppert, Carol Imanuel; Fuhrich, Nicole; Taubert, Helge; Wach, Sven; Breyer, Johannes; Otto, Wolfgang; Burger, Maximilian; Bolenz, Christian; Keck, Bastian; Wullich, Bernd; Hartmann, Arndt; Sikic, Danijel
Erschienen: BMJ, 2020
Erschienen in: Journal for ImmunoTherapy of Cancer
Sprache: Englisch
DOI: 10.1136/jitc-2019-000162
ISSN: 2051-1426
Schlagwörter: Cancer Research ; Pharmacology ; Oncology ; Molecular Medicine ; Immunology ; Immunology and Allergy
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Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Patients and methods</jats:title><jats:p>Gene expression of<jats:italic>CD3Z</jats:italic>,<jats:italic>CD8A</jats:italic>and<jats:italic>CXCL9</jats:italic>, 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The gene expression signature of<jats:italic>CXCL9</jats:italic>,<jats:italic>CD3Z</jats:italic>and<jats:italic>CD8A</jats:italic>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).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The gene expression signature of<jats:italic>CD3Z</jats:italic>,<jats:italic>CD8A</jats:italic>and<jats:italic>CXCL9</jats:italic>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.</jats:p></jats:sec>
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