PAX7-FOXO1 fusion protein–derived peptide antigens (PAX7-FOXO1 peptides)

PAX7-FOXO1 fusion protein–derived peptide antigens are tumor-specific neoantigens resulting from the t(1;13)(p36;q14) chromosomal translocation, a defining genetic event in a subset of alveolar rhabdomyosarcomas (ARMS) (Barr et al., 1993). This translocation fuses the PAX7 gene on chromosome 1 with the FOXO1 (formerly FKHR) gene on chromosome 13, creating a chimeric transcription factor that promotes cell survival and inhibits differentiation. The unique amino acid sequence at the fusion junction is not found in the normal human proteome, making it an ideal target for precision immunotherapy with minimal risk of cross-reactivity with healthy tissues (Rodeberg et al., 2006). These junctional peptides can be loaded onto MHC molecules and presented to the immune system, where they serve as targets for peptide-based vaccines or T-cell receptor (TCR) engineered T-cell therapies. Despite their high specificity, the therapeutic efficacy of targeting these antigens can be challenged by low MHC expression on tumor cells and the inherently low binding affinity of some junctional sequences to common HLA alleles. Current research efforts are focused on optimizing peptide delivery and combining these immunotherapies with checkpoint inhibitors to overcome the immunosuppressive tumor microenvironment.

Other names

PAX7-FKHR fusion peptidesAlveolar rhabdomyosarcoma neoantigensPAX7-FOXO1 junctional peptidest(1;13) fusion antigens

These peptide antigens are processed intracellularly and presented by Major Histocompatibility Complex (MHC) class I molecules on the surface of tumor cells. Once presented, they are recognized by the T-cell receptors (TCRs) of CD8+ cytotoxic T-lymphocytes, which triggers the release of perforins and granzymes, leading to the targeted apoptosis of the PAX7-FOXO1-expressing cancer cells.