Tumor-Associated Macrophages Provide Significant Prognostic Information in Urothelial Bladder Cancer

Abstract

Inflammation is an important feature of carcinogenesis. Tumor-associated macrophages (TAMs) can be associated with either poor or improved prognosis, depending on their properties and polarization. Current knowledge of the prognostic significance of TAMs in bladder cancer is limited and was investigated in this study. We analyzed 184 urothelial bladder cancer patients undergoing transurethral resection of a bladder tumor or radical cystectomy. CD68 (pan-macrophage marker), MAC387 (polarized towards type 1 macrophages), and CLEVER-1/Stabilin-1 (type 2 macrophages and lymphatic/blood vessels) were detected immunohistochemically. The median follow-up time was 6.0 years. High macrophage counts associated with a higher pT category and grade. Among patients undergoing transurethral resection, all studied markers apart from CLEVER-1/Stabilin-1 were associated with increased risk of progression and poorer disease-specific and overall survival in univariate analyses. High levels of two macrophage markers (CD68/MAC387+/+ or CD68/CLEVER-1+/+ groups) had an independent prognostic role after transurethral resection in multivariate analyses. In the cystectomy cohort, MAC387, alone and in combination with CD68, was associated with poorer survival in univariate analyses, but none of the markers were independent predictors of outcome in multivariate analyses. In conclusion, this study demonstrates that macrophage phenotypes provide significant independent prognostic information, particularly in bladder cancers undergoing transurethral resection.

Bladder cancer cells induce immunosuppression of T cells by supporting PD‐L1 expression in tumour macrophages partially through interleukin 10

“…Aside from the IL‐10‐ and PD‐L1‐mediated effects presented in this study, we think that other immunosuppressive mechanisms are present in bladder cancer patients to suppress their antitumour immunity. Following surgical resection, bladder cancer patients who had higher TAM density presented higher risk of tumour recurrence and shorter disease‐free intervals (Ajili et al, ; Bostrom et al, ), which cannot be explained by the direct, tumour cell‐mediated mechanism presented here because the tumour mass was not present. Therefore, further investigations are required for full understanding of the immune regulation in bladder cancer.…”

“…TAMs could also support angiogenesis and increase tumour cell invasion and motility (Qian and Pollard, 2010). Higher density of CD68-expressing TAMs was associated with higher tumour grade and worse survival in bladder cancer patients (Bostrom et al, 2015), as well as poorer response to BCG therapy (Ayari et al, 2009). Importantly, TAMs in many tumours express high levels of the programmed death ligand 1 (PD-L1) (Noy and Pollard, 2014).…”

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

“…Horn et al (2015) showed that a high FOXP3/CD8 ratio within invasive cancer tissue was an independent predictor of poor overall survival after cystectomy [23]. High numbers of CD68+ TAMs were associated with an advanced pT category and high-grade cancer [24], acting as an additional independent factor (CD68/CD3 ratio > 1) with a more than 7-fold higher risk of cancer-specific death on multivariate analysis [25]. Conversely, increased intratumoral CD3+ and CD8+ T-cells were predictive of significantly better overall and disease-free survival [26–27].…”

AMPKα Is Suppressed in Bladder Cancer through Macrophage-Mediated Mechanisms

“…To assess the impact of macrophages on AMPKα, U937 cells which were differentiated with PMA to become macrophage-like cells were utilized because they express similar cell surface markers as the macrophages present in bladder cancer [33], [36], [46]. Treatment of human bladder cell lines with CM from U937 macrophages elicited downregulation of AMPKα1, AMPKα2, and the total AMPKα1/α2 at the protein level but not at the mRNA level.…”