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

// Bo Wang 1, 2, * , Hao Liu 2, * , Xiaoliang Dong 1, * , Shaoxu Wu 2 , Hong Zeng 3 , Zhuowei Liu 4 , Di Wan 2 , Wen Dong 2 , Wang He 2 , Xu Chen 2 , Limin Zheng 5 , Jian Huang 2 , Tianxin Lin 1, 2 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, PR China 2 Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhosngshan) University, Guangzhou, PR China 3 Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen (Zhongshan) University, Guangzhou, PR China 4 Department of Urology, Cancer Center, Sun Yat-Sen (Zhongshan) University, Guangzhou, PR China 5 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen (Zhongshan) University, Guangzhou, PR China * These authors have contributed equally to this work Correspondence to: Tianxin Lin, e-mail: tianxinl@sina.com Jian Huang, e-mail: urolhj@sina.com Keywords: tumor-infiltrating macrophages, CD204, CD169, urothelial cell carcinoma of the bladder (UCB) Received: December 03, 2014 Accepted: April 25, 2015 Published: May 07, 2015 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.