Anti-tumor immune response induced by dendritic cells transduced with truncated PSMA IRES 4-1BBL recombinant adenoviruses

Cancer Lett. 2010 Jul 28;293(2):254-62. doi: 10.1016/j.canlet.2010.01.011. Epub 2010 Feb 9.

Abstract

Up-regulation of receptor-ligand pairs during interaction of a peptide-bound MHC complex on dendritic cells (DCs) with cognate TCR may amplify, sustain, and drive diversity in the ensuing T cell immune response. Members of the TNF ligand superfamily and the TNFR superfamily contribute to this costimulatory molecule signaling. In the present study, we used replication deficient adenoviruses to introduce a tumor-associated Ag (a truncated human prostate-specific membrane antigen (tPSMA)) and the T cell costimulatory molecule 4-1BBL into murine DCs, and observed the ability of these recombinant DCs to elicit tPSMA-directed T-cell responses in vitro and anti-tumor immunity to RM-1-tPSMA in a murine tumor model. Infection of DCs with Ad-tPSMA-IRES-m4-1BBL induced tPSMA-specific proliferative responses and up-regulated CD80 and CD86 s signaling molecules. The cytotoxic T lymphocytes activated by the Ad-tPSMA-IRES-m4-1BBL-transfected DCs showed significantly higher IFN-gamma production and cytotoxicity against the RM-1 cells transfected with tPSMA. Moreover, vaccination of mice with Ad-tPSMA-IRES-m4-1BBL-transfected DCs induced a potent protective and therapeutic anti-tumor immunity to RM-1-tPSMA in a tumor model. These results demonstrated that development of DCs engineered to express tPSMA and 4-1BBL by recombinant adenovirus-mediated gene transfer may offer a new strategy for prostate cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand / immunology*
  • Adenoviridae / genetics
  • Animals
  • Cancer Vaccines / therapeutic use*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Dendritic Cells / immunology*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prostate-Specific Antigen / immunology*
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / therapy
  • T-Lymphocytes, Cytotoxic / immunology
  • Transduction, Genetic
  • Up-Regulation
  • Vaccines, Synthetic / therapeutic use*

Substances

  • 4-1BB Ligand
  • Cancer Vaccines
  • Vaccines, Synthetic
  • Prostate-Specific Antigen