Cancer-derived transforming growth factor-β modulates tumor-associated macrophages in ampullary cancer

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differenti-ate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer. Patients and Methods: TAMs in ampullary cancer were investigated using immunohisto-chemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated in vitro to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer. Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163⁺ cells and that the expression of mature CD68⁺ macro-phages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinfor-matics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68⁺ and more inducible nitric oxide synthase macro-phages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages. Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.