Mutant TP53-derived neoantigen peptides presented by Human Leukocyte Antigen (HLA) (Mutant TP53-HLA complex)

Mutant TP53-derived neoantigen peptides presented by Human Leukocyte Antigen (HLA) are highly specific cancer targets formed when mutated p53 proteins are processed by the proteasome and presented on the cell surface by MHC Class I molecules (Hsiue et al., Science 2021). TP53 is the most frequently mutated gene in human cancers, and certain hotspot mutations (such as R175H, R248Q, or R273H) create shared neoantigens that can be targeted across different patients with the same mutation and HLA type (Lo et al., Science 2022). These complexes are recognized by the immune system as non-self, making them ideal for precision immunotherapies such as T-cell receptor-engineered T-cell (TCR-T) therapy and bispecific T-cell engagers (Hsiue et al., Science 2021). Unlike traditional drugs that target the p53 protein's function, these therapies leverage the immune system to selectively destroy cells displaying the mutant peptide-HLA complex. However, the clinical application is challenged by the extremely low density of these complexes on the tumor cell surface and the potential for tumor resistance through the loss of HLA expression (Hsiue et al., Science 2021; Lo et al., Science 2022).

Other names

p53 neoantigensTP53-HLA complexMutation-associated neoantigens (MANAs) derived from TP53p53-derived peptide-MHC complexesp53-HLA-A*02:01 complexp53-HLA-A*11:01 complex

T-cell mediated cytotoxicity and redirection of T-cells to tumor cells expressing specific mutant p53-HLA complexes (Hsiue et al., Science 2021; Lo et al., Science 2022).