Regulatory T cells in tumor immunity.

Recent studies have revealed that Foxp3(+)CD25(+)CD4(+) regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self-tolerance, play critical roles for the control of antitumor immune responses. For example, a large number of Foxp3(+)Tregs infiltrate into tumors, and systemic removal of Foxp3(+)Tregs enhances natural as well as vaccine-induced antitumor T-cell responses. Tregs are recruited to tumor tissues via chemokines, such as CCL22 binding to CCR4 expressed by Tregs. They appear to expand and become activated in tumor tissues and in the draining lymph nodes by recognizing tumor-associated antigens as well as normal self-antigen expressed by tumor cells. These results indicate that cancer vaccines targeting tumor-associated self-antigens may potentially expand/activate Tregs and hamper effective antitumor immune responses, and that tumor immunity can therefore be enhanced by depleting Tregs, attenuating Treg suppressive function, or rendering effector T cells refractory to Treg-mediated suppression. Recent attempts have indeed demonstrated that combinations of monoclonal antibodies capable of modulating Treg functions synergistically enhance antitumor activity and are more effective than a single monoclonal antibody therapy. Combination therapy targeting a variety of molecules expressed in antigen-presenting cells, effector T cells and Tregs is envisaged to be a promising anticancer immunotherapy.