Efficient simultaneous presentation of NY-ESO-1/LAGE-1 primary and nonprimary open reading frame-derived CTL epitopes in melanoma.
Recent studies have shown that CTL epitopes derived from tumor-associated Ags can be encoded by both primary and nonprimary open reading frames (ORF). In this study we have analyzed the HLA-A2-restricted CD8(+) T cell response to a recently identified CTL epitope derived from an alternative ORF product of gene LAGE-1 (named CAMEL), and the highly homologous gene NY-ESO-1 in melanoma patients. Using MHC/peptide tetramers we detected CAMEL(1-11)-specific CD8(+) T cells in peptide-stimulated PBMC as well as among tumor-infiltrated lymph node cells from several patients. Sorting and expansion of tetramer(+) CD8(+) T cells allowed the isolation of tetramer(bright) and tetramer(dull) populations that specifically recognized the peptide Ag with high and low avidity, respectively. Remarkably, only high avidity CAMEL-specific CTL were able to recognize Ag-expressing tumor cells. A large series of HLA-A2-positive melanoma cell lines was characterized for the expression of LAGE-1 and NY-ESO-1 mRNA and protein and tested for recognition by CAMEL-specific CTL as well as CTL that recognize a peptide (NY-ESO-1(157-165)) encoded by the primary ORF products of the LAGE-1 and NY-ESO-1 genes. This analysis revealed that tumor-associated CD8(+) T cell epitopes are simultaneously and efficiently generated from both primary and nonprimary ORF products of LAGE-1 and NY-ESO-1 genes and, importantly, that this occurs in the majority of melanoma tumors. These findings underscore the in vivo immunological relevance of CTL epitopes derived from nonprimary ORF products and support their use as candidate vaccines for inducing tumor specific cell-mediated immunity against cancer.
Rimoldi
D
D
Ludwig Institute for Cancer Research, Lausanne Branch, Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland. donata.rimoldi@isrec.unil.ch
Rubio-Godoy
V
V
Dutoit
V
V
Lienard
D
D
Salvi
S
S
Guillaume
P
P
Speiser
D
D
Stockert
E
E
Spagnoli
G
G
Servis
C
C
Cerottini
J C
JC
Lejeune
F
F
Romero
P
P
Valmori
D
D
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D000954:Antigens, Surface; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019556:COS Cells; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins; D016366:Open Reading Frames / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; C104948:CTAG1B protein, human; C510162:CTAG2 protein, human; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins