title: Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+T-cell proliferation and survival.
abstract: The CD8+T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (TCM) and effector (TEM) memory cells. TCMcells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance TCMcells and delay terminal differentiation of CD8+T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8+memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8+T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8+T cells, and their inhibition enhances the therapeutically superior TCMphenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8+T-cell exhaustion and preserves naïve and TCMCD8+T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8+T cells are enhanced by maintaining a reservoir of TCMand naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8+T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies.
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA.
authors.forename: Rasha
authors.initials: R
authors.lastname: Abu Eid
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA ; bluebird bio ; Cambridge, MA, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Friedman
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA.
authors.forename: Mikayel
authors.initials: M
authors.lastname: Mkrtichyan
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA ; Duke University ; Durham, NC, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Walens
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA.
authors.forename: William
authors.initials: W
authors.lastname: King
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Janik
authors.affiliation: Georgia Regents University, Cancer Center ; Augusta, GA, USA.
authors.forename: Samir N
authors.initials: SN
authors.lastname: Khleif
keywords: ACT, adoptive cell transfer; Akt; CBA, cytometric bead array; IFNγ, interferon gamma; KLRG-1, killer cell lectin-like receptor subfamily G member 1; KO, knockout; SORP, special order research product; T cells; TCM, central memory; TCR, T-cell receptor; TEM, effector memory; TNF, tumor necrosis factor; Tregs, regulatory T cells; VCT, violet cell trace; WT, wild type; central memory; effector memory; proliferation