TP53-derived neoantigen-MHC class I complex (p53-neoantigen-MHC)

TP53-derived neoantigen peptides presented on MHC class I are tumor-specific antigens resulting from somatic mutations in the TP53 gene, the most commonly mutated gene in human cancer. These neoantigens are formed when mutant p53 proteins are degraded into short peptides and presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, such as HLA-A*02:01. Because these peptides contain specific amino acid substitutions, such as the common R175H mutation, they can be distinguished from wild-type p53 by the immune system, making them ideal targets for precision immunotherapy. Therapeutic approaches targeting these complexes include T-cell receptor-engineered T cells (TCR-T), bispecific T-cell engagers (TCEs), and cancer vaccines. These drugs work by redirecting cytotoxic T lymphocytes to recognize and eliminate cancer cells expressing the specific mutant peptide-MHC complex. A significant challenge in targeting this molecule is the extremely low density of the complex on the cell surface, often occurring at attomole levels. Additionally, the high degree of HLA polymorphism means that each therapeutic agent is typically restricted to patients with a specific HLA genotype. Despite these hurdles, targeting p53 neoantigens offers a way to hit traditionally undruggable intracellular mutations by exploiting the natural antigen presentation pathway.

Other names

p53 mutation-derived neoantigenp53-HLA complexmutant p53 neoepitopep53 pMHCp53-derived peptide-MHC class I complex

T-cell mediated cytotoxicity via recognition of mutation-specific peptides presented on MHC class I molecules