Role of Foxp3-positive Tumor-infiltrating Lymphocytes in the Histologic Features and Clinical Outcomes of Hepatocellular Carcinoma

The role of Foxp3-positive regulatory T cells (Foxp3(+) Tregs) in suppression of antitumoral immune response is well documented in patients with cancer. However, it is not known whether Foxp3(+) Tregs are associated with specific clinicopathologic characteristics of hepatocellular carcinoma (HCC). The aims of the present study were: (1) to investigate the relationship between Foxp3(+) Tregs and histologic differentiation, Edmondson-Steiner (ES) nuclear grade, vascular invasion, and pathologic stage of HCC in patients undergoing surgery for their disease; and (2) to evaluate any Foxp3(+) Treg-defined difference in the risk for tumor recurrence or death. The study sample included 131 histologic sections of HCC. The number of tumor-infiltrating CD3, CD8, and Foxp3(+) lymphocytes was assessed by immunohistochemistry. An increased Foxp3:CD3 ratio was associated with more poorly differentiated HCC (P = 0.0016) and higher ES nuclear grade (P = 0.0407). An increased Foxp3:CD8 ratio was also associated with poorer differentiation (P = 0.0044), higher ES nuclear grade (P = 0.0179), recurrence (P= 0.0183), decreased overall survival (hazard ratio = 1.153; 95% confidence interval, 1.019-1.304; P = 0.0235), and decreased disease-free survival (hazard ratio = 1.138; 95% confidence interval, 1.016- 1.273; P = 0.0249). Tumor size and type of surgery (surgical resection) were associated with decreased disease-free survival on univariate analysis but not on multivariate analysis. In conclusion, a higher concentration of tumor-infiltrating Foxp3(+) Tregs in HCC is associated with higher grade and poorly differentiated tumors and signifies an unfavorable prognosis.