Cytotoxic T-lymphocyte responses in melanoma through in vitro stimulation with the Melan-A peptide analogue A27L: a qualitative analysis.
Modifications in tumour antigen-derived epitopes that stabilize the major histocompatibility complex (MHC)-peptide complex result in enhanced stimulatory capacity and improved immunogenicity of the altered peptide. These epitope analogues are attractive candidates for the development of peptide-based vaccine trials. Any modification, however, in tumour antigens may induce T-cell responses that could either fail to react against the naturally occurring peptides or represent only a subset of the total antigen-specific repertoire. In the present study, we performed a critical analysis of the ability of cytotoxic T-lymphocyte (CTL) clones, derived from two melanoma patients through stimulation with the A27L peptide analogue, to cross-react with the naturally processed Melan-A/MART-1 (Melan-A) peptides in terms of T-cell receptor (TCR) affinity, functional avidity and fine antigen specificity. We found that all the A27L-specific clones analysed possessed a very low avidity for the natural Melan-A peptides, and that their binding affinity for human leukocyte antigen (HLA) tetramers complexed with both the modified and the natural Melan-A peptides did not strictly correlate with their functional avidity. We also observed that these clones were able to cross-recognize both natural Melan-A peptides in one patient, but only one peptide in the second patient. We discuss the capability of the A27L peptide analogue to stimulate all the available Melan-A-specific repertoire.
Palermo
B
B
Experimental Immunology, IRCCS Maugeri Foundation, Pavia, Italy.
Campanelli
R
R
Garbelli
S
S
Mantovani
S
S
Robustelli Della Cuna
G
G
Necker
A
A
Manganoni
A M
AM
Carella
G
G
Rivoltini
L
L
Lantelme
E
E
Giachino
C
C
D000915:Antibody Affinity; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000378:metabolism
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006680:HLA Antigens; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell