Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;3:209–49.

Article  Google Scholar 

Witjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, Hernandez V, Linares Espinos E, Lorch A, Neuzillet Y, et al. European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol. 2021;79(1):82–104.

Article  CAS  PubMed  Google Scholar 

Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102–14.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bellmunt J, Hussain M, Gschwend JE, Albers P, Oudard S, Castellano D, Daneshmand S, Nishiyama H, Majchrowicz M, Degaonkar V, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(4):525–37.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Powles T, Assaf ZJ, Davarpanah N, Banchereau R, Szabados BE, Yuen KC, Grivas P, Hussain M, Oudard S, Gschwend JE, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432–7.

Article  CAS  PubMed  Google Scholar 

Eckstein M, Strissel P, Strick R, Weyerer V, Wirtz R, Pfannstiel C, Wullweber A, Lange F, Erben P, Stoehr R, et al. Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy. J Immunother Cancer. 2020;8:1.

Article  Google Scholar 

Pfannstiel C, Strissel PL, Chiappinelli KB, Sikic D, Wach S, Wirtz RM, Wullweber A, Taubert H, Breyer J, Otto W, et al. The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes. Cancer Immunol Res. 2019;7(6):923–38.

Article  CAS  PubMed  Google Scholar 

Taber A, Christensen E, Lamy P, Nordentoft I, Prip F, Lindskrog SV, Birkenkamp-Demtroder K, Okholm TLH, Knudsen M, Pedersen JS, et al. Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat Commun. 2020;11(1):4858.

Article  CAS  PubMed  PubMed Central  Google Scholar 

van Wilpe S, Sultan S, Gorris MAJ, Somford DM, Kusters-Vandevelde HVN, Koornstra RHT, Gerritsen WR, Simons M, van der Heijden AG, de Vries IJM, et al. Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome. Cancer Immunol Immunother. 2022. https://doi.org/10.1007/s00262-022-03234-0.

Article  PubMed  PubMed Central  Google Scholar 

Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, Van Der Heijden MS, Szabados B, Pous AF, Gravis G, Herranz UA, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019;25(11):1706–14.

Article  CAS  PubMed  Google Scholar 

Galsky MD, Wang L, Saci A, Szabo PM, Gong Y, Zhu J. Epithelial-mesenchymal transition (EMT), T cell infiltration, and outcomes with nivolumab (nivo) in urothelial cancer (UC). Ann Oncol. 2017;28:v297.

Article  Google Scholar 

Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015;25(4):198–213.

Article  PubMed  Google Scholar 

Sikic D, Weyerer V, Geppert CI, Bertz S, Lange F, Taubert H, Wach S, Schmitz-Draeger BJ, Wullich B, Hartmann A, et al. Utility of stromal tumor infiltrating lymphocyte scoring (sTILs) for risk stratification of patients with muscle-invasive urothelial bladder cancer after radical cystectomy. Urol Oncol. 2022;2(63):19–63.

Google Scholar 

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Leblond MM, Zdimerova H, Desponds E, Verdeil G. Tumor-associated macrophages in bladder cancer: biological role, impact on therapeutic response and perspectives for immunotherapy. Cancers. 2021;13:18.

Article  Google Scholar 

Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sjodahl G, Lovgren K, Lauss M, Chebil G, Patschan O, Gudjonsson S, Mansson W, Ferno M, Leandersson K, Lindgren D, et al. Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol Oncol. 2014;32(6):791–7.

PubMed  Google Scholar 

Fu H, Zhu Y, Wang Y, Liu Z, Zhang J, Xie H, Fu Q, Dai B, Ye D, Xu J. Identification and validation of stromal immunotype predict survival and benefit from adjuvant chemotherapy in patients with muscle-invasive bladder cancer. Clin Cancer Res. 2018;24(13):3069–78.

Article  CAS  PubMed  Google Scholar 

Taubert H, Eckstein M, Epple E, Jung R, Weigelt K, Lieb V, Sikic D, Stohr R, Geppert C, Weyerer V, et al. Immune cell-associated protein expression helps to predict survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and optional adjuvant chemotherapy. Cells. 2021;10:1.

Article  Google Scholar 

Board WCoTE. Urinary and male genital tumours—who classification of tumours. 5th ed. France: IARC Publications; 2022.

Google Scholar 

Koll FJ, Schwarz A, Kollermann J, Banek S, Kluth L, Wittler C, Bankov K, Doring C, Becker N, Chun FKH, et al. CK5/6 and GATA3 defined phenotypes of muscle-invasive bladder cancer: impact in adjuvant chemotherapy and molecular subtyping of negative cases. Front Med. 2022;9:875142.

Article  Google Scholar 

Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878.

Article  PubMed  PubMed Central  Google Scholar 

Strack E, Rolfe PA, Fink AF, Bankov K, Schmid T, Solbach C, Savai R, Sha W, Pradel L, Hartmann S, et al. Identification of tumor-associated macrophage subsets that are associated with breast cancer prognosis. Clin Transl Med. 2020;10(8):e239.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Viratham Pulsawatdi A, Craig SG, Bingham V, McCombe K, Humphries MP, Senevirathne S, Richman SD, Quirke P, Campo L, Domingo E, et al. A robust multiplex immunofluorescence and digital pathology workflow for the characterisation of the tumour immune microenvironment. Mol Oncol. 2020;14(10):2384–402.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C. Cutoff Finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7(12):e51862.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Powles T, Loriot Y, Ravaud A, Vogelzang NJ, Duran I, Retz M, De Giorgi U, Oudard S, Bamias A, Koeppen H, et al. Atezolizumab (atezo) vs. chemotherapy (chemo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): immune biomarkers, tumor mutational burden (TMB), and clinical outcomes from the phase III IMvigor211 study. J Clin Oncol. 2018;36(6):409–409.

Article  Google Scholar 

Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22.

Article  CAS  PubMed  Google Scholar 

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, Hinoue T, Laird PW, Hoadley KA, Akbani R, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–56.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kamoun A, de Reynies A, Allory Y, Sjodahl G, Robertson AG, Seiler R, Hoadley KA, Groeneveld CS, Al-Ahmadie H, Choi W, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2019. https://doi.org/10.1016/j.eururo.2019.09.006.

Article  PubMed  PubMed Central  Google Scholar 

Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, Yeh JJ, Milowsky MI, Iyer G, Parker JS, et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA. 2014;111(8):3110–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Ferno M, Ringner M, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18(12):3377–86.