Dendritic cells engineered to express defined allo-HLA peptide complexes induce antigen-specific cytotoxic T cells efficiently killing tumour cells.
Most tumour-associated antigens (TAA) are non-mutated self-antigens. The peripheral T cell repertoire is devoid of high-avidity TAA-specific cytotoxic T lymphocytes (CTL) due to self-tolerance. As tolerance is major histocompatibility complex-restricted, T cells may be immunized against TAA presented by a non-self human leucocyte antigen (HLA) molecule and transferred to cancer patients expressing that HLA molecule. Obtaining allo-restricted CTL of high-avidity and low cross-reactivity has, however, proven difficult. Here, we show that dendritic cells transfected with mRNA encoding HLA-A*0201, efficiently present externally loaded peptides from the antigen, Melan-A/MART-1 to T cells from HLA-A*0201-negative donors. CD8(+) T cells binding HLA-A*0201/MART-1 pentamers were detected already after 12 days of co-culture in 11/11 donors. The majority of cells from pentamer(+) cell lines were CTL and efficiently killed HLA-A*0201(+) melanoma cells, whilst sparing HLA-A*0201(+) B-cells. Allo-restricted CTL specific for peptides from the leukaemia-associated antigens CD33 and CD19 were obtained with comparable efficiency. Collectively, the results show that dendritic cells engineered to express defined allo-HLA peptide complexes are highly efficient in generating CTL specifically reacting with tumour-associated antigens.
Stronen
E
E
Institute of Immunology, Rinkshospitalet Medical Center and The University of Oslo, Oslo, Norway.
Abrahamsen
I W
IW
Gaudernack
G
G
Wälchli
S
S
Munthe
E
E
Buus
S
S
Johansen
F-E
FE
Lund-Johansen
F
F
Olweus
J
J
D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D010455:Peptides / Q000276:immunology; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007519:Isoantigens; D010455:Peptides