Non-traditional immunogens and their application to immunotherapy.
Abstract
In the process of identification of tumor-associated antigens that elicit immunological responses in cancer patients, evidence for the existence of non-traditional immunogens with little sequence homologies to normal open reading frames has been revealed. The generation of non-traditional immunogens is either transcriptionally controlled (by activation of pepton, cryptic promoter activation, splicing events, or chromosomal rearrangements) or translationally controlled (by frameshift mutation or translation from an alternative open reading frame). The non-traditional immunogen may possess either an epitope (antigenic determinant of a true antigen) or mimotope (mimics or structural equivalents of epitopes of a true antigen). In vitro studies have revealed the presence of mimotope-specific CD8+ T-cells in cancer patients, suggesting that these mimotopes could represent a natural alternative to T-cells. In cases in which tumor antigens are overexpressed in cancer, mimotopes can overcome tolerance by activating T-cell receptors (TCRs) that originally had low avidity for their respective tumor antigens. Peptide mimotopes have been shown to possess the MHC binding motif and cause efficient activation of T-cells. Indeed, mimotopes from an epitope of melanoma cell-adhesion molecule can elicit both humoral and cytotoxic T-lymphocyte immune responses in mice. Furthermore, studies suggest that mimotopes could be excellent targets for cancer immunotherapy. This review summarizes the discovery and functional characteristics of non-traditional immunogens, in particular mimotopes in cancer immunotherapy.