Assessment of immunogenicity of human Melan-A peptide analogues in HLA-A*0201/Kb transgenic mice.
Previous studies have shown that substitution of single amino acid residues in human Melan-A immunodominant peptides Melan-A27-35 and Melan-A26-35 greatly improved their binding and the stability of peptide/HLA-A*0201 complexes. In particular, one Melan-A peptide analogue was more efficient in the generation of Melan-A peptide-specific and melanoma-reactive CTL than its parental peptide in vitro from human PBL. In this study, we analyzed the in vivo immunogenicity of Melan-A natural peptides and their analogues in HLA-A*0201/Kb transgenic mice. We found that two human Melan-A natural peptides, Melan-A26-35 and Melan-A27-35, were relatively weak immunogens, whereas several Melan-A peptide analogues were potent immunogens for in vivo CTL priming. In addition, induced Melan-A peptide-specific mouse CTL cross-recognized natural Melan-A peptides and their analogues. More interestingly, these mouse CTL were also able to lyse human melanoma cell lines in vitro in a HLA-A*0201-restricted, Melan-A-specific manner. Our results indicate that the HLA-A*0201/Kb transgenic mouse is a useful animal model to perform preclinical testing of potential cancer vaccines, and that Melan-A peptide analogues are attractive candidates for melanoma immunotherapy.
Men
Y
Y
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Miconnet
I
I
Valmori
D
D
Rimoldi
D
D
Cerottini
J C
JC
Romero
P
P
D000483:Alleles; D000818:Animals; D000951:Antigens, Neoplasm; D001120:Arginine; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D007279:Injections, Subcutaneous; D007930:Leucine; D008213:Lymphocyte Activation / Q000235:genetics; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015234:HLA-A Antigens; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D009842:Oligopeptides; D001120:Arginine; D007930:Leucine