Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex

T cell responsiveness to an epitope is affected both by its affinity for th e presenting MHC molecule and the affinity of the MHC-peptide complex for T CR. One limitation of cancer immunotherapy is that natural tumor antigens e licit relatively weak T cell responses, in part because high-affinity T cel ls are rendered tolerant to these antigens. We report here that amino acid substitutions in a natural MHC class I-restricted tumor antigen that increa se the stability of the MHC-peptide-TCR complex are significantly more pote nt as tumor vaccines. The improved immunity results from enhanced in vivo e xpansion of T cells specific for the natural tumor epitope. These results i ndicate peptides that stabilize the MHC-peptide-TCR complex may provide sup erior antitumor immunity through enhanced stimulation of specific T cells.