Reduced infiltration of tumor-associated macrophages in human prostate cancer: Association with cancer progression

Tumor-associated macrophages (TAMs) are highly active immune effector cells that may either positively or negatively regulate the growth of various malignant cells, depending on the biological context. However, the role of TAMs in human prostate cancer progression is unclear. TAMs were immunohistochemically labeled using a monoclonal (CD68) antibody in radical prostatectomy specimens derived from 81 prostate cancer patients. CD68-positive cells were counted with the aid of a microscope and expressed as macrophage index (M(φ)I), including TAMs/mm² total tumor tissue (M(φ)I(total)), TAMs/mm² tumor stroma (M(φ)I(stroma)), and TAMs/mm² cancer cell area (M(φ)I(cancer)). M(φ)Is were analyzed in association with patients' clinical and pathological stage, recurrence status, and histological grade of the cancer. There were significant inverse relationships between M(φ)I(total) and M(φ)I(stroma) and clinical stage (P = 0.016 and P = 0.006, respectively). Reduced M(φ)I(total) was also associated with the presence of positive lymph nodes (P = 0.010). Interestingly, although all of the M(φ)Is differed between Gleason score groups, only M(φ)I(cancer) was positively associated with Gleason score. Univariate analysis of M(φ)I(total) and multivariate analysis of M(φ)I(total) with specific pathological markers revealed that M(φ)I(total) was an independent predictor for disease-free survival after surgery (Cox proportional hazard model, P = 0.044 and P = 0.007, respectively). For patients with high M(φ)I(total) (≥185.8, the mean M(φ)I(total) value), the disease-free probability 5 years after surgery was 0.75, which was significantly higher than for those with low M(φ)I(total) (0.31, P = 0.0008). Additional immunohistochemical studies that evaluated cytotoxicity-related biomarkers in stroma-associated mononuclear cells suggested reduced functional activities in highly aggressive prostate cancer compared with less aggressive disease. Our results indicate that reduced M(φ)I(total) is a novel prognostic marker for prostate cancer.