C/EBP mediates the maturation and antitumor functions of macrophages in human hepatocellular carcinoma

Recent studies have suggested that therapeutic upregulation of CCAAT/enhancer binding protein alpha (C/EBP alpha) prevents hepatocellular carcinoma (HCC) progression. However, the mechanisms underlying this outcome are not fully understood. In this study, we investigated the expression and functional roles of C/EBP alpha in human HCC, with a focus on monocytes/macrophages (M phi s). Paraffin-embedded tissues were used to visualize C/EBP alpha expression and analyze the prognostic value of C/EBP alpha(+) monocytes/M phi s in HCC patients. The underlying regulatory mechanisms were examined using human monocyte-derived M phi s. The results showed that the expression of C/EBP alpha on monocytes/M phi s was significantly decreased in intra-tumor tissues compared to the corresponding peri-tumor tissues. C/EBP alpha(+) monocytes/M phi s displayed well-differentiation and antitumor capacities, and the accumulation of these cells in tissue was associated with antitumor immune responses and predicted longer overall survival (OS) of HCC patients. Mechanistic studies demonstrated that C/EBP alpha was required for M phi maturation and HLA-DR, CD169 and CD86 expression, which initiates antitumor cytotoxic T-cell responses; however, these effects were inhibited by monocyte autocrine IL-6- and IL-1 beta-induced suppression of mTOR1 signaling. Reprogramming M phi s via the upregulation of C/EBP alpha may provide a novel strategy for cancer immunotherapy in patients with HCC.