T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms

Mol Ther. 2010 Nov;18(11):2006-17. doi: 10.1038/mt.2010.185. Epub 2010 Sep 14.


Adoptive transfer of antigen-specific cytotoxic T lymphocytes has shown promise for the therapy of cancer. However, tumor-specific T cells are susceptible to diverse inhibitory signals from the tumor microenvironment. The Akt/protein kinase B plays a central role in T-cell proliferation, function, and survival and we hypothesized that expression of constitutively active Akt (caAkt) in T cells could provide resistance to many of these tumor-associated inhibitory mechanisms. caAkt expression in activated human T cells increased proliferation and cytokine production, a likely result of their sustained expression of nuclear factor-κB (NF-κB) and provided resistance to apoptosis by upregulating antiapoptotic molecules. caAkt expressing T cells (caAkt-T-cells) were also relatively resistant to suppression by and conversion into regulatory T cells (Tregs). These characteristics provided a survival advantage to T cells cocultured with tumor cells in vitro; CD3/28-stimulated T cells expressing a chimeric antigen receptor (CAR) specific for disialoganglioside (GD2) that redirected their activity to the immunosuppressive, GD2-expressing neuroblastoma cell line, LAN-1, resisted tumor-induced apoptosis when co-expressing transgenic caAkt. In conclusion, caAkt-transduced T cells showed resistance to several evasion strategies employed by tumors and may therefore enhance the antitumor activity of adoptively transferred T lymphocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Western
  • Cell Proliferation
  • Flow Cytometry
  • Gangliosides / metabolism
  • Humans
  • Lymphocyte Activation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neuroblastoma / immunology
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Transduction, Genetic
  • Transforming Growth Factor beta / pharmacology
  • Tumor Burden / immunology
  • Tumor Cells, Cultured


  • Gangliosides
  • NF-kappa B
  • RNA, Messenger
  • Transforming Growth Factor beta
  • sialogangliosides
  • Proto-Oncogene Proteins c-akt