Increased CD4+CD69+CD25- T cells in patients with hepatocellular carcinoma are associated with tumor progression

Background and Aim: A new subset of Treg cells, CD4(+)CD69(+)CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC). Methods: We detected CD4(+)CD69(+)CD25(-) T cells and its expression of CCR6 and transforming growth factor-beta 1 (TGF-beta 1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+)CD69(+)CD25(-) T cells in HCC tissues were also analyzed. Results: CD4(+)CD69(+)CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% +/- 0.42% vs 4.55% +/- 0.33% and 5.15% +/- 0.36%, P < 0.0001). The percentage of peripheral CD4(+)CD69(+)CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+)CD69(+)CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-b1 positive cells in CD4(+)CD69(+)CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+)CD69(+)CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+)CD69(+)CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients. Conclusions: Increased CD4(+)CD69(+)CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+)CD69(+)CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC.