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, M(F)-DeltaAkt, is sufficient for maturation and survival of murine bone marrow-derived DCs in vivo. M(F)-DeltaAkt-transduced DCs enhanced T-cell proliferation, activation and long-term memory responses, enabling eradication of large pre-established lymphomas and aggressive B16 melanomas. Human myeloid DCs expressing constitutively active M(F)-DeltahAkt 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.
Park
Dongsu
D
Department Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Lapteva
Natalia
N
Seethammagari
Mamatha
M
Slawin
Kevin M
KM
Spencer
David M
DM
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053898:Biosynthetic Pathways; D019496:Cancer Vaccines / Q000096:biosynthesis / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008223:Lymphoma / Q000628:therapy; D008545:Melanoma / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012878:Skin Neoplasms / Q000628:therapy
D019496:Cancer Vaccines; D024101:Mitochondrial Proteins; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human