Abstract
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.
Highlights
Bladder cancer is the most common type of urological tumor and more than 90% of patients present as urothelial cell carcinoma of the bladder (UCB) [1,2]
Using two-color immunofluorescence analyses, we observed that CD204+ CD68+ Mφs in stromal regions (Mφs) and CD169+ Mφs could be observed among the CD68+ Mφs (Supplementary Fig. 1)
We found that CD68+ Mφs were distributed throughout the tissues, and were more frequent in ST than in INT regions of UCB tissues (35 ± 26 and 15 ± 14 cells/field, respectively; Fig. 1; n = 302)
Summary
Bladder cancer is the most common type of urological tumor and more than 90% of patients present as urothelial cell carcinoma of the bladder (UCB) [1,2]. Tumor-infiltrating macrophages (Mφs) have been shown to have both pro- and antitumorigenic functions, which could be a consequence of the different tumor microenvironments that promote their differentiation into distinct subpopulations [7,8]. CD68, a pan-Mφ marker, is widely used to evaluate Mφ density in diverse types of human tumors; the expression of CD68 does not allow for discrimination between diverse Mφ phenotypes, which can be associated with different patient prognosis [10,11,12,13]. A more detailed characterization of distinct Mφ subpopulations might provide an opportunity to eliminate protumoral Mφs or harness antitumoral Mφs in human cancers
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