CD8(+) T-cell response to NY-ESO-1: Relative antigenicity and in vitro immunogenicity of natural and analogue sequences

We have shown previously that HLA-A*0201 melanoma patients can frequently d evelop a CTL response to the cancer testis antigen NY-ESO-1, In the present study, we have analyzed in detail the relative antigenicity and in vitro i mmunogenicity of natural and modified NY-ESO-1 peptide sequences. The resul ts of this analysis revealed that, although suboptimal for binding to the H LA-A*0201 molecule, peptide NY-ESO-1 157-165 is, among natural sequences, v ery efficiently recognized by specific CTL clones derived from three melano ma patients. In contrast, peptides NY-ESO-1: 157-167 and NY-ESO-1 155-163, which bind very strongly to HLA-A*0201, are recognized less efficiently. In agreement with previous data, substitution of peptide NY-ESO-1 157-165 COO H-terminal C with various other amino acids resulted in a significantly inc reased binding to HLA-A*0201 molecules as well as in an increased CTL recog nition, although variable at the clonal level. Among natural peptides, NY-E SO-1 157-165 and NY-ESO-1 157-167 exhibited good in vitro immunogenicity, w hereas peptide NY-ESO-1 155-163 was poorly immunogenic, The fine specificit y of interaction between peptide NY-ESO-1 C165A, HLA-A*0201, and T-cell rec eptor was analyzed at the molecular level using a series of variant peptide s containing single alanine substitutions. The findings reported here have significant implications for the formulation of NY-ESO-1-based vaccines as well as for the monitoring of either natural or vaccine-induced NY-ESO-1-sp ecific CTL responses in cancer patients.