T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms.
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.
Sun
Jiali
J
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
Dotti
Gianpietro
G
Huye
Leslie E
LE
Foster
Aaron E
AE
Savoldo
Barbara
B
Gramatges
Maria M
MM
Spencer
David M
DM
Rooney
Cliona M
CM
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005434:Flow Cytometry; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D047368:Tumor Burden / Q000276:immunology; D014407:Tumor Cells, Cultured
D005732:Gangliosides; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C025447:sialogangliosides; D051057:Proto-Oncogene Proteins c-akt