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

The CD8 T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (T) and effector (T) memory cells. T cells 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 T cells 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 T phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8 T-cell exhaustion and preserves naïve and T CD8 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 T and 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.