In vivo expansion of naïve CD4 ⁺CD25 ^high FOXP3 ⁺ regulatory T cells in patients with colorectal carcinoma after IL-2 administration

Regulatory T cells (T _reg cells) are increased in context of malignancies and their expansion can be correlated with higher disease burden and decreased survival. Initially, interleukin 2 (IL-2) has been used as T-cell growth factor in clinical vaccination trials. In murine models, however, a role of IL-2 in development, differentiation, homeostasis, and function of T _reg cells was established. In IL-2 treated cancer patients a further T _reg-cell expansion was described, yet, the mechanism of expansion is still elusive. Here we report that functional T _reg cells of a naïve phenotype - as determined by CCR7 and CD45RA expression - are significantly expanded in colorectal cancer patients. Treatment of 15 UICC stage IV colorectal cancer patients with IL-2 in a phase I/II peptide vaccination trial further enlarges the already increased naïve T _reg-cell pool. Higher frequencies of T-cell receptor excision circles in naïve T _reg cells indicate IL-2 dependent thymic generation of naïve T _reg cells as a mechanism leading to increased frequencies of T _reg cells post IL-2 treatment in cancer patients. This finding could be confirmed in naïve murine T _reg cells after IL-2 administration. These results point to a more complex regulation of T _reg cells in context of IL-2 administration. Future strategies therefore might aim at combining IL-2 therapy with novel strategies to circumvent expansion and differentiation of naïve T _reg cells.