In vivo Expansion of Naive CD4+CD25high 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 naive 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 naive T-reg-cell pool. Higher frequencies of T-cell receptor excision circles in naive T-reg cells indicate IL-2 dependent thymic generation of naive 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 naive 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 naive T-reg cells.