Identification of a FOXP3+CD3+CD56+ population with immunosuppressive function in cancer tissues of human hepatocellular carcinoma

The liver resident lymphoid population is featured by the presence of a large number of CD3(+)CD56(+) cells referred as natural T cells. In human hepatocellular carcinoma (HCC) patients, the natural T cells were found to be sharply decreased in tumor (5.871 ± 3.553%) versus non-tumor (14.02 ± 6.151%) tissues. More intriguingly, a substantial fraction of the natural T cells (22.76 ± 18.61%) assumed FOXP3 expression. These FOXP3-expressing CD3(+)CD56(+) cells lost the expression of IFN-γ and perforin, which are critical for the effector function of natural T cells. On the other hand, they acquired surface expression of CD25 and CTLA-4 typically found in regulatory T (Treg) cells. Consistent with the phenotypic conversion, they imposed an inhibitory effect on anti-CD3-induced proliferation of naive T cells. Further studies demonstrated that transforming growth factor β1 (TGF-β1) could effectively induce FOXP3 expression in CD3(+)CD56(+) cells and the cells were thus endowed with a potent immunosuppressive capacity. Finally, Kaplan-Meier analysis revealed that the relative abundance of FOXP3-expressing CD3(+)CD56(+) cells in tumor tissues was significantly correlated with the survival of HCC patients. In conclusion, the present study identified a new type of regulatory immune cells whose emergence in liver cancer tissues may contribute to tumor progression.