Dendritic cells adenovirally-transduced with full-length mesothelin cDNA elicit mesothelin-specific cytotoxicity against pancreatic cancer cell lines in vitro

Cancer Lett. 2011 Jun 1;305(1):32-9. doi: 10.1016/j.canlet.2011.02.013.

Abstract

Mesothelin (MSLN) is an attractive candidate as a molecular target for pancreatic cancer immunotherapy. The purpose of this study was to demonstrate that cytotoxic T lymphocytes (CTLs) generated from peripheral blood mononuclear cells (PBMCs) by stimulation with genetically-modified dendritic cells (DCs) expressing MSLN could produce specific anti-tumor immunity against pancreatic cancer cells endogenously expressing MSLN. MSLN-specific CTLs were generated from PBMCs of healthy donors by in vitro stimulation with DCs adenovirally-transduced with the full-length MSLN gene (DC-AxCAMSLN). The cytotoxic activity was tested using a 4-h (51)Cr-release assay. The pancreatic cancer cell lines (PK1, CfPAC1, AsPC1), a lymphoblastoid cell lines (LCL) transduced with the MSLN gene, and LCL pulsed with MSLN-epitope peptides were used as target cells. MSLN-specific CTLs induced by in vitro stimulation with DC-AxCAMSLN killed pancreatic cancer cell lines expressing MSLN in an HLA-restricted fashion. These CTLs also showed cytotoxic activity against autologous LCL pulsed with multiple MSLN-derived epitope peptides. In addition, CD8(+) T cells, as well as CD4(+) T cells, sorted from these CTLs showed significant production of interferon-γ when stimulated with DC-AxCAMSLN. The in vitro stimulation of PBMCs with DCs transduced with the full-length MSLN gene elicited a potent MSLN-specific cytotoxic activity against pancreatic cancer cell lines endogenously expressing MSLN by recognizing multiple MSLN epitopes and activating both CD8(+) T cells and CD4(+) helper T cells. These results therefore suggest the potential of developing future clinical applications of the vaccines using genetically-modified DCs expressing MSLN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / immunology*
  • DNA, Complementary / genetics
  • Dendritic Cells / immunology*
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / immunology*
  • Genetic Vectors
  • Humans
  • Immunohistochemistry
  • Immunotherapy, Active / methods*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / therapy
  • T-Lymphocytes, Cytotoxic / immunology
  • Transduction, Genetic

Substances

  • Cancer Vaccines
  • DNA, Complementary
  • GPI-Linked Proteins
  • mesothelin