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Development of a Murine Mutant Ras CD8⁺ CTL Peptide Epitope Variant That Possesses Enhanced MHC Class I Binding and Immunogenic Properties

Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

We recently identified a murine mutant Ras p21 CD8⁺ CTL epitope reflecting residues 4 to 12, containing the mutation of Gly to Val at codon 12, that bound weakly to H-2K^d in vitro and generated a weak primary CTL response in immunized BALB/c mice. Here, we explored the hypothesis that specific modifications to the Ras_4–12 peptide sequence can improve MHC binding, leading to enhanced immunogenicity without altering immune specificity. We synthesized Ras_4–12 peptides in which Val at residue 12 was replaced with the more dominant H-2K^d C-terminus anchor residue Leu or Ile. In functional H-2K^d binding assays, Ras_4–12(L12 or I12) peptide variants competed more effectively than the Ras_4–12(V12) peptide. Ras_4–12(L12 or I12) peptide variants enhanced both in vitro cytotoxicity and proliferation responses of anti-Ras_4–12 CTL compared with the mutant Ras_4–12(V12) peptide. Additionally, the Ras_4–12(L12) peptide variant induced a quantitatively greater T cell response in vivo compared with that produced by Ras_4–12(V12) as determined by IFN- production. Mice immunized with Ras_4–12(L12) peptide elicited CD8⁺ CTL activity specific for target cells presenting the Ras_4–12(V12) epitope exogenously and endogenously. Moreover, both anti-Ras_4–12(V12)-derived and anti-Ras_4–12(L12)-derived CTL lines were similar insofar as their TCR usage and amino acid contact residues in the Ras_4–12(V12) peptide. These experiments demonstrate that modifications can be introduced in tumor-specific peptide epitopes to enhance both in vitro and in vivo immunogenicity. The design of oncogene-specific peptide epitope variants as immunogens may accelerate the generation of anti-tumor T cell responses for cancer immunotherapy.

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