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

Abstract

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. © 2012 Beyer et al.