Artikel
Cytotoxic T-Cell related gene expression signature predicts improved outcome in muscle-invasive urothelial bladder cancer patients following radical cystectomy and adjuvant chemotherapy
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Autoren
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Markus Eckstein
- Universitätsklinikum Erlangen, Institut für Pathologie
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Danijel Sikic
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
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Ralph M. Wirtz
- STRATIFYER Molecular Pathology GmbH, Molekulare Pathologie, Köln
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Pamela Strissel
- Universitätsklinikum Erlangen, Frauenklinik
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Carolin Pfannstiel
- Universitätsklinikum Erlangen, Institut für Pathologie
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Adrian Wullweber
- Universitätsklinikum Erlangen, Institut für Pathologie
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Fabienne Lange
- Universitätsklinikum Erlangen, Institut für Pathologie
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Philipp Erben
- Medizinische Fakultät Mannheim, Universität Heidelberg
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Robert Stöhr
- Universitätsklinikum Erlangen, Institut für Pathologie
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Simone Bertz
- Universitätsklinikum Erlangen, Institut für Pathologie
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Carol I. Geppert
- Universitätsklinikum Erlangen, Institut für Pathologie
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Nicole Fuhrich
- Universitätsklinikum Erlangen, Institut für Pathologie
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Veronika Weyerer
- Universitätsklinikum Erlangen, Institut für Pathologie
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Helge Taubert
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
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Franziska Erlmeier
- TU München, Institut für Pathologie
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Johannes Breyer
- Universität Regensburg, Klinik für Urologie
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Wolfgang Otto
- Universität Regensburg, Klinik für Urologie
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Bastian Keck
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
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Sven Wach
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
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Frank Kunath
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
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Reiner Strick
- Universitätsklinikum Erlangen, Frauenklinik
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Arndt Hartmann
- Universitätsklinikum Erlangen, Institut für Pathologie
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Bernd Wullich
- Universitätsklinikum Erlangen, Klinik für Urologie und Kinderurologie
| Veröffentlicht: | 8. April 2019 |
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Gliederung
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Background: Recently, distinct immune phenotypes in muscle-invasive bladder cancer (MIBC) correlating with patient survival and outcome were defined. This study was conducted to develop a simple, robust diagnostic assay based on RT-qPCR to predict outcome of patients undergoing radical cystectomy and adjuvant chemotherapy.
Material and methods: Gene expression of CD3Z, CD8A and CXCL9 was assessed by RT-qPCR in a cohort of 187 patients with MIBC treated by radical cystectomy (adjuvant chemotherapy n= 49). A gene expression signature was derived by hierarchical-clustering and then validated in 407 MIBC patients of the TCGA-cohort. Benefit of platinum-containing chemotherapy was assessed by applying the gene expression signature in a pooled analysis of our cohort and the TCGA cohort consisting of 125 patients. To validate a correlation of gene expression with distinct immune cell populations the quantitative amount of CD3, CD8, CD56 (NK-Cells) and CD68 (macrophages) positive immune cells was assessed on regionally designed TMAs as well as sTILs (stromal tumor infiltrating lymphocytes) on HE slides. Results of the TCGA cohort were validated with immune cell population analysis via CIBERSORT and sTIL-scoring on digitalized HE-slides. Furthermore, immune-ness was correlated with intrinsic bladder cancer subtypes according to the MDACC-subtyping approach.
Results: Gene expression of CXCL9, CD3Z and CD8A correlates moderately to strongly with quantitative amounts of specific immune cell populations as well as with sTILs scored on HE slides in MIBC (finding cohort: r-range: 0.44-0.74; validation cohort [TCGA]: r-range: 0.56-0.82). Patients with high expression of CD3Z, CD8A and CXCL9 are preferentially of basal differentiation and show favorable 5-year survival rates of 68% (finding cohort, “inflamed high”: HR=0.22) and 55% (TCGA, “Inflamed high”: HR=0.60). Uninflamed tumors are characterized by mainly luminal differentiation and low 5-year survival rate of 28% (finding cohort) and 36% (TCGA). Compared to uninflamed tumors, patients undergoing adjuvant chemotherapy (pooled cohort; n=125; composed of patients with extravesical tumors or/and lymph node metastasis) with “inflamed high” tumors showed a favorable 5-year survival rate of 64% (HR=0.27).
Conclusion: The diagnostic three-gene signature consisting of CD3Z, CD8A and CXCL9 is able to identify patients with favorable prognosis after radical cystectomy and adjuvant chemotherapy. Prospective validation is ongoing.
