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.
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).
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.
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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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020;395:1268–77.
Lughezzani G, Burger M, Margulis V, Matin SF, Novara G, Roupret M, et al. Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Eur Urol. 2012;62:100–14.
Meng ZW, Pan W, Hong HJ, Chen JZ, Chen YL. Modified staging classification for intrahepatic cholangiocarcinoma based on the sixth and seventh editions of the AJCC/UICC TNM staging systems. Medicine. 2017;96:e7891.
Soukup V, Capoun O, Cohen D, Hernandez V, Babjuk M, Burger M, et al. Prognostic performance and reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in non-muscle-invasive bladder cancer: a European association of urology non-muscle invasive bladder cancer guidelines panel systematic review. Eur Urol 2017;72:801–13.
Necchi A, Lo Vullo S, Mariani L, Moschini M, Hendricksen K, Rink M, et al. Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology-Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration. BJU Int. 2018;121:252–9.
Seisen T, Krasnow RE, Bellmunt J, Roupret M, Leow JJ, Lipsitz SR, et al. Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma. J Clin Oncol. 2017;35:852–60.
Quhal F, Mori K, Sari Motlagh R, Laukhtina E, Pradere B, Roupret M, et al. Efficacy of neoadjuvant and adjuvant chemotherapy for localized and locally advanced upper tract urothelial carcinoma: a systematic review and meta-analysis. Int J Clin Oncol. 2020;25:1037–54.
Tanaka N, Kikuchi E, Shirotake S, Kanao K, Matsumoto K, Kobayashi H, et al. The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy: a multi-institutional study. Eur Urol. 2014;65:227–34.
Tanaka N, Kikuchi E, Kanao K, Matsumoto K, Shirotake S, Miyazaki Y, et al. A multi-institutional validation of the prognostic value of the neutrophil-to-lymphocyte ratio for upper tract urothelial carcinoma treated with radical nephroureterectomy. Ann Surg Oncol. 2014;21:4041–8.
Giraldo NA, Sanchez-Salas R, Peske JD, Vano Y, Becht E, Petitprez F, et al. The clinical role of the TME in solid cancer. Br J Cancer. 2019;120:45–53.
Xie HY, Shao ZM, Li DQ. Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis. Chin J Cancer. 2017;36:36.
Park JH, McMillan DC, Edwards J, Horgan PG, Roxburgh CS. Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer. Oncoimmunology. 2016;5:e1098801.
Liu J, Liu J, Li J, Chen Y, Guan X, Wu X, et al. Tumor-stroma ratio is an independent predictor for survival in early cervical carcinoma. Gynecol Oncol. 2014;132:81–6.
Lou E, Vogel RI, Hoostal S, Klein M, Linden MA, Teoh D, et al. Tumor-stroma proportion as a predictive biomarker of resistance to platinum-based chemotherapy in patients with ovarian cancer. JAMA Oncol. 2019;5:1222–4.
Huijbers A, Tollenaar RA, v Pelt GW, Zeestraten EC, Dutton S, McConkey CC, et al. The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial. Ann Oncol. 2013;24:179–85.
Chen Y, Zhang L, Liu W, Liu X. Prognostic significance of the tumor-stroma ratio in epithelial ovarian cancer. Biomed Res Int. 2015;2015:589301.
Huang J, Zhang L, Wan D, Zhou L, Zheng S, Lin S, et al. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct Target Ther. 2021;6:153.
Idorn M, Olsen M, Halldorsdottir HR, Skadborg SK, Pedersen M, Hogdall C, et al. Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction. Oncoimmunology. 2018;7:e1412029.
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–37.
Xu B, Li XL, Ye F, Zhu XD, Shen YH, Huang C, et al. Development and validation of a nomogram based on perioperative factors to predict post-hepatectomy liver failure. J Clin Transl Hepatol. 2021;9:291–300.
Zhong W, Wang B, Yu H, Lin J, Xia K, Hou W, et al. Serum CCL27 predicts the response to Bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer. Oncoimmunology. 2020;9:1776060.
Chen J, Zhong W, Yang M, Hou W, Wang X, Xia K, et al. Development and validation of a PD-L1/PD-1/CD8 axis-based classifier to predict cancer survival of upper tract urothelial carcinoma after radical nephroureterectomy. Cancer Immunol Immunother. 2021;70:2657–68.
Cheng S, Zhong W, Xia K, Hong P, Lin R, Wang B, et al. Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: a retrospective multicenter study (TSU-02 study). Oncoimmunology. 2021;10:1861737.
Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48:W509–W14.
Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17:218.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. 2005;102:15545–50.
Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.
Zheng C, Zheng L, Yoo JK, Guo H, Zhang Y, Guo X, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017;169:1342–56. e16
Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:2128–39.
Peng C, Liu J, Yang G, Li Y. The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system. J Gastroenterol. 2018;53:606–17.
Birtle AJ, Chester JD, Jones RJ, Jenkins B, Johnson M, Catto JW, et al. Updated outcomes of POUT: a phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol. 2021;39:455.
van Wyk HC, Roseweir A, Alexander P, Park JH, Horgan PG, McMillan DC, et al. The relationship between tumor budding, tumor microenvironment, and survival in patients with primary operable colorectal cancer. Ann Surg Oncol. 2019;26:4397–404.
Zunder SM, van Pelt GW, Gelderblom HJ, Mancao C, Putter H, Tollenaar RA, et al. Predictive potential of tumour-stroma ratio on benefit from adjuvant bevacizumab in high-risk stage II and stage III colon cancer. Br J Cancer. 2018;119:164–9.
Karpathiou G, Vieville M, Gavid M, Camy F, Dumollard JM, Magne N, et al. Prognostic significance of tumor budding, tumor-stroma ratio, cell nests size, and stroma type in laryngeal and pharyngeal squamous cell carcinomas. Head Neck. 2019;41:1918–27.
Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–66.
Mhaidly R, Mechta-Grigoriou F. Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer. Immunol Rev. 2021;302:259–72.
Yoo SY, Park HE, Kim JH, Wen X, Jeong S, Cho NY, et al. Whole-slide image analysis reveals quantitative landscape of tumor-immune microenvironment in colorectal cancers. Clin Cancer Res. 2020;26:870–81.
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.
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).
Ethics approval and consent to participate
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