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

Abstract

Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses still are 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, 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. 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 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 Treg both in naïve and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg-dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Treg. We show that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg-depletion.

PKB/Akt-dependent regulation of inflammation in cancer

“…A similar effect was confirmed with a grafted myeloma mouse model [90]. Additionally, inhibition of PKB with MK-2206 selectively suppressed Treg proliferation and consequently improved anti-tumor activity in a tumor-specific vaccine model [91]. These preclinical studies all point towards a promising strategy with co-targeting PKB for cancer cell specific inhibition as well as improved immune editing.…”

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

“…We conclude that upon PD-1 blockade, upregulation of Tim-3 is mediated by enhanced TCR-proximal signaling to the PI3K/IAkt/mTOR pathway. Based on a previous report that selective PI3K or Akt inhibition results in enhanced antitumor immune response in a HPVC TC-1 mouse model in a Treg-dependent manner without attenuating conventional T cell activity, 31 our work raises a potential therapeutic strategy of combining anti-PD-1 mAb with selective PI3K/Akt inhibition to promote antitumor immunity by overcoming compensatory Tim-3 upregulation. …”

Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+T-cell proliferation and survival

“…Furthermore, we have recently shown that PI3K/Akt pathway inhibitors selectively target Tregs with resultant significant enhancement of antitumor immune response, including a significant decrease in Treg cells and increase in CD8 C T cells within the tumor microenvironment. 23 Therefore, using Akt inhibitors can simultaneously enhance the effector arm by augmenting the memory CD8…”