Oncogenic mutations in ras create HLA-A2.1 binding peptides but affect their extracellular antigen processing.

Published

Journal Article

Point mutations in oncogene products such as ras may create neoantigenic determinants recognizable by T lymphocytes as tumor antigens, that could be marshalled to eliminate a tumor by inducing specific cytotoxic T lymphocytes (CTL) with an appropriate vaccine. Peptide-pulsed dendritic cells are a promising new approach to cancer vaccines. For such an approach to work, the determinant must be appropriately processed to the right size fragment and be presented by an appropriate HLA molecule. We have investigated both of these issues for a series of ras codon 12 and 13 point mutations that contain sequences predicted to bind to HLA-A2.1, the most common class I HLA molecule. We find that not only do the different mutations affect binding to HLA-A2.1, but also they affect extracellular antigen processing in two ways: by influencing the trimming of flanking residues from the longer sequence and by influencing the susceptibility of the optimal decamer to further proteolytic degradation. The influence of internal residues on cleavage of flanking residues downstream demonstrates the importance of distant interactions between separated amino acid side chains and/or conformational effects in determining antigen processing. These results may be important in designing an effective vaccine to induce mutant ras-specific tumor immunity.

Full Text

Duke Authors

Cited Authors

  • Smith, MC; Pendleton, CD; Maher, VE; Kelley, MJ; Carbone, DP; Berzofsky, JA

Published Date

  • August 1997

Published In

Volume / Issue

  • 9 / 8

Start / End Page

  • 1085 - 1093

PubMed ID

  • 9263005

Pubmed Central ID

  • 9263005

International Standard Serial Number (ISSN)

  • 0953-8178

Digital Object Identifier (DOI)

  • 10.1093/intimm/9.8.1085

Language

  • eng

Conference Location

  • England