Interesting. Don't think I ever put this abstract up, as it didn't hone in on delta (perhaps the manuscript did, don't know). But Dr. Khleif appears to be a driver behind the anti-PD-1 that Medivation just licensed. His group is immersed in stuff that is of interest.....
(edit: inhibitors included triciribine, MK-2206, wortmannin and IC87114, the latter being PI3Kdelta selective)
Cancer Immunol Res. 2014 Jul 30. [Epub ahead of print]
Selective Inhibition of Regulatory T Cells by Targeting the PI3K-Akt Pathway.
Abu-Eid R1, Samara RN2, Ozbun L2, Abdalla MY2, Berzofsky JA2, Friedman KM3, Mkrtichyan M1, Khleif SN4.
1Georgia Regents University Cancer Center, Augusta, Georgia.
2National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
3bluebird bio, Cambridge, Massachusetts.
4Georgia Regents University Cancer Center, Augusta, Georgia. SKhleif@gru.edu.
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 selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation 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 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 Tregs. We show that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg depletion. |
