Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus.
Dendritic cells (DC) are potent stimulators of primary T cell responses. In this study, we demonstrate that DC, genetically engineered to express the MART-1/Melan-A (MART-1) tumor-associated Ag, express MART-1 mRNA and protein, correctly process and present the HLA-A2.1-restricted immunodominant MART-1 peptide (MART-1(27-35)), and serve as potent stimulators of MART-1-specific CTL in vitro. A replication-defective E1-deleted adenovirus (AdV) was constructed that expresses MART-1 (AdVMART1). Transduced DC produce full length MART-1 mRNA as well as MART-1 protein. AdVMART1 does not significantly down-regulate cell surface class I expression despite having an intact E3 region. Transduction of an HLA-A2-positive/MART-1-negative cell line with AdVMART1 renders these cells sensitive to lysis by CTL specific for the MART-1(27-35) immunodominant peptide. In addition, DC transduced with AdVMART1 stimulated MART-1(27-35)-specific tumor-infiltrating lymphocytes to synthesize IFN-gamma. Finally, AdVMART1-transduced DC were able to generate MART-1(27-35) peptide-specific, class I-restricted CTL in PBL cultures from normal donors. This study supports the use of tumor Ag-engineered DC in genetic immunotherapy.
Butterfield
L H
LH
Division of Surgical Oncology, University of California Los Angeles Medical Center 90095-1782, USA.
Jilani
S M
SM
Chakraborty
N G
NG
Bui
L A
LA
Ribas
A
A
Dissette
V B
VB
Lau
R
R
Gamradt
S C
SC
Glaspy
J A
JA
McBride
W H
WH
Mukherji
B
B
Economou
J S
JS
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005818:Genetic Engineering; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D058965:MART-1 Antigen; C105787:MART-1-Melan-A(27-35) epitope; C548667:MLANA protein, human; D009363:Neoplasm Proteins