Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome

Abstract

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC). While recent studies point towards the existence of different fibroblast subsets, no comprehensive analyses linking different fibroblast markers to UBC patient survival have been performed so far. Through immunohistochemical analysis of five selected fibroblast markers, namely alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet derived growth factor receptor-alpha and-beta (PDGFRa,-b), this study investigates their association with survival and histopathological characteristics in a cohort of 344 UBC patients, involving both, muscleinvasive and non-muscle-invasive cases. The data indicates that combinations of stromal markers are more suited to identify prognostic patient subgroups than single marker analysis. Refined stromamarker-based patient stratification was achieved through cluster analysis and identified a FAPdominant patient cluster as independent marker for shorter 5-year-survival (HR(95% CI)2.25(1.08-4.67), p = 0.030). Analyses of interactions between fibroblast and CD8a-status identified a potential minority of cases with CD90-defined stroma and high CD8a infiltration showing a good prognosis of more than 80% 5-year-survival. Presented analyses point towards the existence of different stroma-cell subgroups with distinct tumor-modulatory properties and motivate further studies aiming to better understand the molecular tumor-stroma crosstalk in UBC. The estimated incidence of urinary bladder cancer (UBC) worldwide was about 550.000 new cases and 200.000 deaths in 2018 1 , with highest incidences indicated in developed areas 2. Given that the prevalence of UBC is several times higher than the incidence, it represents a major burden for health care systems. Carcinomas originating from the urothelium, the inner surface of the bladder, represent the most common type of bladder cancer 3,4. Approximately 70% of all newly diagnosed cases are classified as non-muscle-invasive bladder cancer disease, while about 30% of patients have already muscle-invasive tumors with 10-15% of them being metastatic 5-8. Reported 5-year recurrence rates of non-muscle invasive cases range between 40-70% among the highest recurrence rates of solid tumors 3,9. Multidisciplinary approaches have been established in order to improve patient management and to decrease the mortality rate, but still treatment strategies for UBC remain controversial. A better understanding of the mechanisms underlying tumor progression is crucial and novel prognostic and predictive markers as well as therapeutic targets need to be identified 10,11. Recent research efforts on UBC aimed mostly to decipher molecular drivers of an invasive tumor phenotype through description of genetic varieties, and with the introduction of checkpoint inhibitory immunotherapy, awareness has also risen for tumor infiltrating leukocytes 12,13. However, little attention was given the interaction of tumor cells and non-leukoc...

New Roadmaps for Non-muscle-invasive Bladder Cancer With Unfavorable Prognosis

“…Indeed, innate and adaptive immune cells as well as stromal components surrounding tumor may have a prognostic value especially for evaluating BCG responsiveness in NMIBCs. Recently, Mezheyeuski et al ( 2020 ) analyzed five cancer-associated fibroblast (CAF) markers, stroma-based, alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet-derived growth factor receptor-alpha and -beta (PDGFRa-b) with survival and histopathological characteristics in 344 BC patients (231 NMIBCs, 113 MIBCs). Cluster analysis of stromal marker-based patient stratification identified a FAP-dominant patient cluster as an independent marker for shorter 5-year survival [Hazard Ratio, HR (95% confidence interval) 2.25 (1.08–4.67), p = 0.030].…”

“…Cluster analysis of stromal marker-based patient stratification identified a FAP-dominant patient cluster as an independent marker for shorter 5-year survival [Hazard Ratio, HR (95% confidence interval) 2.25 (1.08–4.67), p = 0.030]. Other studies on immunomodulatory properties rely on CD8a and revealed a potential minority of cases with CD90-defined stroma and high CD8a T cell infiltration showing a good prognosis of more than 80% 5-year survival (Mezheyeuski et al, 2020 ). Chu et al ( 2020 ) described an innovative approach using indoleamine 2,3-dioxgenase 1 (IDO1) inhibitors in combination with immunotherapies in MIBCs and NMIBCs; the use of specific molecules such as indoximod, epacadostat, and linrodostat permit the immune microenvironment manipulation and increase of sensitivity to existing therapies with the goal of preventing the immune escape of cancer (Chu et al, 2020 ).…”

“…In the United States, urothelial carcinoma of the bladder represents the most frequent urothelial neoplasm, and the fourth most common cancer in men (McConkey and Lerner, 2019;Siegel et al, 2020). Approximatively 70% of bladder cancer (BC) are non-muscle-invasive (NMIBCs), also known as "superficial" cancer, whereas advanced stages are muscle-invasive BCs (MIBCs) or metastatic BCs (Kamat et al, 2016).…”

“…The standard of care recommends for low-risk NMIBCs only the transurethral resection of the bladder (TURB); for intermediateand high-risk NMIBCs, standard of care recommends the transurethral resection of the bladder (TURB) with or without Bacillus Calmette-Guérin (BCG) immune or chemotherapy (Babjuk et al, 2019). On the contrary, MIBCs undergo radical cystectomy, radiotherapy, and/or chemotherapy even alone (Babjuk et al, 2019;McConkey and Lerner, 2019). Genitourinary cancers are the most likely responsive to immunotherapy (Lalani and Sonpavde, 2019); however, about 20-30% of BCs have unfavorable to very unfavorable prognoses (Babjuk et al, 2019).…”

Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

“…Thus, increasing evidence suggests that it may be expressed by some epithelial tumor cells and, also, by additional cell types of the tumor microenvironment, like macrophages, mature adipocytes and mesenchymal stromal cells [23]. Recent studies on fibroblast heterogeneity have demonstrated that FAP is not homogenously expressed on tumor fibroblasts but, rather, expressed on yet-to-be fully defined subsets of fibroblasts [16,24]. Immune-regulatory mechanisms remain to be fully identified but have been suggested to include the secretion of immune-modulatory CXCL12; the expression of OX40L, PD-L2 and JAM2 and the induction of CTLA4 and PD1 in regulatory T cells [12,16,25].…”