AbstractCytotoxic T lymphocytes (CTL) recognize peptides presented at the cell surface in association with major histocompatibility complex (MHC) class I molecules. The finding that peptides binding to MHC class I molecules share common amino acid motifs renders feasible the selection of antigenic peptides by simply scanning protein sequences, and thus, provides the possibility of inducing CTL to pre‐defined specificities. Tumor cells possess antigens known to generate MHC class I‐restricted CD8+CTL responses. Thus, these antigens represent good targets to induce tumor‐specific immunity. Among these antigens, the p53 tumor suppressor gene product is an attractive candidate for cancer immunotherapy. Mutations in the p53 gene have been found to be very frequently associated with a malignant transformation and often lead to p53 protein overexpression. Thus, we investigated the possibility of inducing CTL to wild‐type or mutant p53 peptides in a BALB/c (H‐2d) mouse model. Peptides possessing the H2‐Kdbinding motif were selected and tested for binding to the H‐2Kdmoleculesin vitro.Synthetic peptides p53122–130wild‐type or “mutant” (Lys → Glu substitution at position 129) were shown to be the best binder peptides and were tested for their immunogenicity in mice. H‐2Kd‐restricted p53‐specific CD8+CTL were generated following immunization of mice with either wild‐type (wt) p53122–130or mutant (mut) p53122–130(E129) peptides. Only low‐affinity CTL can be obtained by immunization with thewtsequence. In contrast, CTL elicited with themutpeptide recognized themutsequence at a 10–100‐fold lower concentration. This indicates that CTL elicited with themutpeptide recognized themutsequence very efficiently, whereas thewtsequence is poorly recognized, if at all. Taken together, these results thus suggest that p53‐specific tumor immunotherapy may be successful only if the
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