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Molecular Diagnostics

The tumour-associated stroma correlates with poor clinical outcomes and immunoevasive contexture in patients with upper tract urothelial carcinoma: results from a multicenter real-world study (TSU-01 Study)

Abstract

Background

In this real-world study, we aimed to elucidate the predictive value of tumour-associated stroma for clinical prognostic and therapeutic response in upper tract urothelial carcinoma (UTUC) by reviewing the clinicopathologic characteristics of 1015 UTUC patients through a nationwide multicenter analysis.

Methods

The tumour–stroma ratio (TSR) was assessed based on tissue sections stained for hematoxylin and eosin (H&E), and patients were further stratified into stroma-high (>50% stroma) and stroma-low group (≤50% stroma). Kaplan–Meier curve and Cox regression hazard analysis were conducted to assess the survival outcomes of UTUC patients. Bioinformatics analysis and immunostaining analysis were applied to portray the tumour microenvironment (TME).

Results

Stroma-high UTUC was significantly associated with poorer survival outcomes and inferior chemotherapeutic responsiveness. Our established nomogram achieved a high prognostic accuracy in predicting overall survival and cancer-specific survival in both of the discovery cohort (area under the curve [AUC] 0.663 and 0.712) and the validation cohort (AUC 0.741 and 0.747). Moreover, stroma-high UTUC was correlated with immunoevasive TME accompanied by increased cancer-associated fibroblasts, tumour-associated macrophages and, conspicuously a cluster of highly exhausted CD8+ T cells.

Conclusion

Our results showed stroma-high UTUC was associated with an inferior prognosis and an immunoevasive TME with exhausted CD8+ T cells in UTUC patients. Our TSR-based nomogram could be used to refine prognosis and inform treatment decisions of patients with UTUC.

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Fig. 1: Flowchart of the study.
Fig. 2: Association of the tumour-associated stroma with cancer survival outcome.
Fig. 3: The relationship between tumour-associated stroma and benefit of adjuvant chemotherapy (ACT) in patients with Stage II–IV upper tract urothelial carcinoma (UTUC).
Fig. 4: Stroma-high tumours were characterised by abundant cancer-associated fibroblasts (CAFs).
Fig. 5: Characterisation of the immunoevasive tumour microenvironment in stroma-high tumours.
Fig. 6: Construction of a TSR-based survival nomogram for upper tract urothelial carcinoma (UTUC).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Dr. Qun He, from the Department of Pathology, Peking University First Hospital, for his assistance with IHC and IF score.

Funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81825016, 81961128027, 81902586, 81772719, 81772728); Guangdong Provincial Natural Science Foundation (2021A1515011541); Guangdong Provincial Clinical Research Center for Urological Diseases (2020B1111170006); Key Laboratory of Malignant Tumour Gene Regulation and Target Therapy of Guangdong Higher Education Institutes (Grant No. KLB09001); Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (Grant No. 013-163); The National Key Research and Development Program of China (Grant No. 2018YFA0902803); The Key Areas Research and Development Program of Guangdong (Grant No. 2018B010109006).

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Authors

Contributions

LHX, WLZ, PH and CCL performed experiments, statistical analysis and drafted the manuscript. KX, MY, RCL and SDC analysed and interpretation of the data. BW, KX, MY and JYC provided technical and material support. LLM, XSL, LQZ and JH provided study supervision and revised the manuscript. JH and TXL designed the study.

Corresponding authors

Correspondence to Xuesong Li, Liqun Zhou, Jian Huang or Tianxin Lin.

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All patients signed an informed consent before surgery that permitted the usage of resected tumours and clinical profiles in research, under the condition of anonymity. The study was approved by the ethics committee of each institution (SYSEC-KY-KS-2022-32), and conducted in accordance with the Declaration of Helsinki. Signed written informed consent was obtained from all patients.

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Xu, L., Zhong, W., Li, C. et al. The tumour-associated stroma correlates with poor clinical outcomes and immunoevasive contexture in patients with upper tract urothelial carcinoma: results from a multicenter real-world study (TSU-01 Study). Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02049-1

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