Tregs, Helios and tumor immunity: the sun has not yet risen

T regulatory cells (Tregs) suppress immune activation and play a critical role in the maintenance of self-tolerance. However, Tregs are enriched in the tumor microenvironment, suppress immune activation and effectively inhibit anti-tumor responses (1). Thus, depletion or blockade of Tregs has been explored as a potential target for cancer immunotherapy. As Tregs were originally defined as CD4+CD25+ T cells, the first attempts to deplete Tregs targeted CD25, the IL2R α-chain. While the results of some mouse studies, with or without vaccination, indicated successful prevention or eradication of tumors, results of human studies have been mixed (1-4). Thus, other approaches to target Tregs are being explored as potential cancer immunotherapies. Tregs differentially express a number of surface receptors and these have been implicated in Treg suppressor function that could serve as targets for immunotherapy (CTLA-4, GITR, OX40, CCR4, FR4 and TIGIT). However, all of these molecules are also up-regulated on activated T cells and it is unclear, in most cases, if antibody therapy depletes Tregs, reverses Treg-mediated suppression, enhances anti-tumor T effector (Teff) cells, or a combination of all three. In fact, the anti-tumor effects of both anti-CTLA-4 mAb and anti-OX40 mAb require their Fc portion to mediate ADCC depletion of Tregs (5-8).