Mutant p53 peptide–Major Histocompatibility Complex class I complex (mutp53-MHC I)

Mutant p53 peptide–Major Histocompatibility Complex (MHC) class I complexes are tumor-specific neoantigens presented on the surface of malignant cells. In many cancers, missense mutations in the TP53 gene lead to the accumulation of stable mutant p53 proteins, which are processed by the proteasome into short peptides (Hsiue et al., 2021, Science). These peptides are then loaded onto MHC class I molecules and displayed on the cell surface, where they can be recognized by the immune system (Lo et al., 2020, Cancer Discovery). Because these specific peptide-MHC combinations are absent on healthy cells, they represent highly specific targets for immunotherapy, particularly for T-cell receptor (TCR)-based therapies and bispecific antibodies. These therapeutic agents are designed to bind the mutant p53-MHC complex with high affinity, triggering T-cell mediated lysis of the tumor cell (Vogelstein et al., 2021, Science). However, the clinical application of these targets is challenged by the low density of the complexes on the cell surface and the requirement for specific HLA alleles in patients (Hsiue et al., 2021, Science). Despite these hurdles, targeting mutant p53-MHC complexes remains a promising strategy for treating a wide range of TP53-mutated solid tumors.

Other names

p53 neoantigen-MHC complexMutant p53-HLA complexp53-derived peptide-MHC class I complexp53-MHC I complex

Recognition of the mutant p53 peptide presented by MHC class I by engineered T-cell receptors (TCRs) or bispecific antibodies, leading to T-cell mediated cytotoxicity against tumor cells (Hsiue et al., 2021, Science).