High CD204(+) tumor-infiltrating macrophage density predicts a poor prognosis in patients with urothelial cell carcinoma of the bladder

Macrophages (Mφs) are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study attempted to investigate the prognostic values of various tumor-infiltrating Mφ phenotypes in patients with urothelial cell carcinoma of the bladder (UCB), with a focus on Mφ tissue microlocalization. Mφs were assessed by immunohistochemistry in tissues from 302 UCB patients using CD68 as a pan-Mφ marker, and CD204 and CD169 as robust pro- and anti-tumoral Mφ phenotype markers, respectively. Our data showed that these Mφ phenotypes were predominately distributed in stromal (ST) rather than in intratumoral (INT) regions (all P < 0.0001). Surprisingly, CD204 and CD169 can be co-expressed by the same CD68(+) Mφs. Kaplan-Meier analysis revealed that all INT- and ST-infiltrating CD204(+) or CD169(+) Mφ densities were inversely associated with overall survival (all P < 0.01). By multivariate analysis, ST-infiltrating CD204(+) Mφ density emerged as an independent prognostic factor for overall survival (HR, 1.981; P = 0.022). Moreover, the density of ST-infiltrating CD204(+) Mφs was positively associated with the tumor size (P = 0.001), tumor stage (P < 0.0001), nodal metastasis (P < 0.0001), and histological grade (P < 0.0001). Our findings suggest that CD204(+) Mφs might play detrimental protumoral roles and represent the predominant Mφ phenotype in human bladder cancer.