Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses are still needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, regulatory T cells (Treg). Although the depletion of Tregs has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought. We found that PI3K–Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells (Tconv). Our results clearly show selectiveinvitroinhibitionofactivation(asrepresented byadecreaseindownstreamsignaling)andproliferation of Tregs in comparison with Tconvs when treated with different Akt and PI3K inhibitors. This effect has been observed in both human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Tregs in both na€ � ve and tumor-bearing mice. Furthermore, these PI3K–Akt inhibitors ledtoasignificanttherapeuticantitumoreffect,whichwasshowntobeTregdependent.Here,wereporttheuseof PI3K–AktpathwayinhibitorsaspotentagentsfortheselectivedepletionofsuppressiveTregs.Weshowthatthese inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg depletion. Cancer Immunol Res; 2(11); 1080–9. � 2014 AACR.