Tumor protein p53-derived peptide–Major Histocompatibility Complex (p53-pMHC)

Tumor protein p53-derived peptide–Major Histocompatibility Complex (p53-pMHC) refers to the cell-surface presentation of p53 fragments by MHC Class I molecules, which serves as a primary signal for CD8+ T cell recognition (PMID: 33658587). In healthy cells, p53 is maintained at low levels, but in many cancers, p53 is either mutated or overexpressed, leading to an increased density of these complexes on the tumor cell surface (PMID: 30635454). These complexes are highly attractive therapeutic targets because they allow the immune system to see intracellular oncogenic changes that are otherwise inaccessible to standard antibody therapies. Current therapeutic approaches include TCR-engineered T cells (TCR-T) and bispecific T-cell engagers designed to bind specific p53 mutation-derived neoantigens, such as the common R175H mutation presented by HLA-A*02:01 (PMID: 33649166). By specifically targeting these pMHC complexes, drugs aim to direct a potent, localized cytotoxic T-cell response against malignant cells while sparing healthy tissue. However, the effectiveness of these therapies can be limited by the high polymorphism of HLA molecules and the potential for immune evasion through the loss of antigen presentation machinery (PMID: 28459414).

Other names

p53-HLA complexp53 peptide-MHC class I complexp53 neoantigen-MHCp53-derived epitope-MHCp53-MHC-I complex

Therapeutic agents such as TCR-T cells or bispecific antibodies bind specifically to the p53 peptide presented within the groove of the MHC Class I molecule. This binding event mimics or enhances natural T-cell recognition, leading to the formation of an immunological synapse, the release of cytotoxic granules (perforin and granzymes), and the subsequent induction of apoptosis in the target tumor cell (PMID: 33649166, PMID: 33658587).