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

Nat Biotechnol. 2006 Dec;24(12):1581-90. doi: 10.1038/nbt1262. Epub 2006 Dec 3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Biosynthetic Pathways
  • Cancer Vaccines / biosynthesis
  • Cancer Vaccines / pharmacology*
  • Carboxylic Ester Hydrolases / metabolism
  • Cell Differentiation
  • Cell Survival*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Down-Regulation / immunology*
  • Humans
  • Immunotherapy / methods
  • Lymphoma / therapy
  • Melanoma / therapy
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Skin Neoplasms / therapy


  • Cancer Vaccines
  • Mitochondrial Proteins
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Carboxylic Ester Hydrolases
  • PTH2 protein, human