Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer

Activated T regulatory (Treg) cells are potent suppressors that mediate immune tolerance. We investigated the relationship between activated Treg cells and the progression of human colon cancer. We designed a cross-sectional study of CD4+Foxp3+ T cells from peripheral blood, primary tumor and nontumor colon tissue of 42 patients with colon cancer and correlated the percentages of different subgroups of Treg cells with colon cancer stage. The phenotypes, cytokine-release patterns and suppression ability of these Treg cells were analyzed. We found that Treg cells increased significantly in both peripheral blood and cancer tissue. In addition, the Treg cells expressed significantly lower levels of CCR7, CD62L and CD45RA in comparison to normal volunteers. Further dividing Treg cells into subgroups based on Foxp3 and CD45RA expression revealed that both activated Treg cells (Foxp3hiCD45RA-) and nonsuppressive Treg cells (Foxp3loCD45RA-), but not resting Treg cells (Foxp3lowCD45RA+), increased in the peripheral blood and cancer tissue of patients with colon cancer. Only the activated Treg cells expressed significantly higher levels of tumor necrosis factor receptor 2 and cytotoxic T-cell antigen-4. Activated Treg cells, however, secreted significantly lower levels of effector cytokines (interleukin-2, tumor necrosis factor-a and interferon-?) than did resting Treg cells and nonsuppressive cells upon ex vivo stimulation. Activated, but not resting, Treg cells in cancer tissue correlated with tumor metastases. In summary, we confirmed that activated Treg cells are a distinct subgroup with effector memory phenotype and fully functional regulatory activity against human colorectal cancer immunity.