An essential role for Akt1 in dendritic cell function and tumor immunotherapy

Current dendritic cell (DC) vaccine preparations involving ex vivo differentiation and maturation produce short-lived, transiently active DCs that may curtail T-cell responses in vivo. We demonstrate that Akt1, downregulation of which decreases DC lifespan, is critical for proinflammatory signal-mediated DC survival and maturation. Lipopolysaccharide or CD40 signaling stabilizes Akt1, promoting both activation and Bcl-2-dependent survival of DCs. Expression of a potent allele encoding a lipid raft targeted Akt1, MF-Delta Akt, is sufficient for maturation and survival of murine bone marrow-derived DCs in vivo. MF-Delta Akt transduced DCs enhanced T-cell proliferation, activation and long- term memory responses, enabling eradication of large preestablished lymphomas and aggressive B16 melanomas. Human myeloid DCs expressing constitutively active MF-Delta hAkt also survived significantly longer and promoted antigen-specific T-cell responses. Thus, Akt1 is a critical regulator of DC lifespan, and its manipulation in DCs can improve the clinical efficacy of DC-based tumor vaccines.