Despite the strides that immune therapy has made in mediating tumor regression, the clinical effect is often transient, and more durable responses are still needed. The temporary nature of the immune response is attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, T regulatory cells (Treg). Although the depletion of Treg 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. Here, we found that PI3K-Akt pathway inhibitors selectively inhibit Treg with minimal effect on conventional T cells (Tconv). Our results clearly show selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation of Treg in comparison to Tconv cells when treated with different Akt and PI3K inhibitors. This effect was observed both in human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Treg both in naïve and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors lead to a significant therapeutic anti-tumor effect, which was shown to be Treg dependent. In this work, we report using PI3K-Akt pathway inhibitors as potent selective agents for the depletion of suppressive Treg. These inhibitors are shown to enhance the anti-tumor immune response and are therefore promising potential Treg-depletion clinical reagents.
- Received May 14, 2014.
- Revision received June 23, 2014.
- Accepted July 21, 2014.
- Copyright © 2014, American Association for Cancer Research.