Enhanced therapeutic efficacy and memory of tumor-specific CD8 T cells by ex vivo PI3K-δ inhibition

Inhibition of specific Akt isoforms in CD8^þ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8^þ T-cell differentiation and assessed the potential use of PI3K isoform–specific inhibitors to favorably condition CD8^þ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen–specific CD8þ T cells was assessed in the presence of PI3K-a, -b, or -d inhibitors. Inhibition of PI3K-d, but not PI3K-a or PI3K-b, delayed terminal differentiation of CD8^þ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after ex vivo PI3K-d inhibition in CD8^þ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function, and survival of CD8^þ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies.