Induction of cytotoxic T-cell responses against immunoglobulin V region-derived peptides modified at human leukocyte antigen-A2 binding residues

Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides de rived from the immunoglobulin (Ig) V region in some but not all patients. T he main reason for this appears to be the low peptide-binding affinity of I g-derived peptides to major histocompatibility complex (MHC) class I molecu les and their resulting low immunogenicity. This might be improved by conse rvative amino acid modifications at the MHC-binding residues of the peptide s (heteroclitic peptides). In this study, it was found that in 18 Ig-derive d peptides, that heteroclitic peptides from the Ig gene with improved bindi ng to human leukocyte antigen (HLA)-A*0201 can be used to improve CTL respo nses. Amino acid substitution substantially increased predicted binding aff inity, and there was a strong correlation between predicted and actual bind ing to HLA-A*0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increa sed killing of antigen-p resenting cells pulsed with the native peptide. Su rprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic p eptide compared with the native peptide. CTLs generated against heterocliti c peptides could kill patients' tumor cells, showing that Ig-derived peptid es can be presented by the tumor cell and that the failure to mount an immu ne response (among other reasons) likely results from the low immunogenicit y of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune r esponses, and that they might be useful tools for enhancing immunotherapy a pproaches to treating B-cell malignant diseases. (C) 2001 by The American S ociety of Hematology.