T-cell epitope clustering in different structural regions of cancer/testis antigens

Abstract

T-cell epitope predictions based on MHC-binding peptide affinities are considered as a valuable step in vaccine design. We have applied programs for epitope and disorder predictions on 642 proteins from various taxonomic groups. Epitope frequencies for both HLA-I and HLA-II-binding nonamer peptides were higher in ordered than in disordered protein regions. Epitopes appertaining to ordered protein regions were prevalently hydrophobic. Cancer/testis antigens (CTA) are potential cancer-vaccines candidates, because they are aberrantly expressed in several types of cancer, while normal expression is restricted to testicular germ cells which do not express HLA-I antigens. Epitope frequency in ordered and disordered protein regions was analysed for several immunogenic CTA, mostly from the MAGE-A, NY-ESO and SSX families that have been previously intensively studied in cellular immune response. Majority of predicted epitopes, presented by HLA-I and HLA-II molecules, are localized in ordered protein regions. In long disordered protein sequences epitopes are frequently flanking potential disorder-to-order transition elements. These results correspond with the locations of experimentally determined epitopes. The CD4+ response to naturally processed HLA-II-presented epitopes from cancer/testis antigen MAGE-A3 were found to be promiscuous for several DRB1 allels, and localized in the central, ordered region of MAGE-A3 antigen, comprising of amino acids 107-293.