Mutant tumor protein p53 peptide–human leukocyte antigen complex (Mutant TP53–HLA complex)

Mutant tumor protein p53 (TP53) peptide–human leukocyte antigen (HLA) complexes are neoantigens presented on the surface of malignant cells. TP53 is a master tumor suppressor gene that is mutated in approximately half of all human cancers, often resulting in hotspot mutations like R175H, R248W, or R273H (Hsiue et al., 2021, Science). These mutations lead to the synthesis of altered proteins that are degraded by the intracellular proteasome into mutant peptides, which are then loaded onto HLA Class I molecules and transported to the cell membrane (Lo et al., 2019, JCI). Because these specific peptide-HLA configurations are absent in healthy tissues, they represent highly specific targets for precision immunotherapy. Current therapeutic strategies include T-cell receptor (TCR) engineered T-cells and TCR-mimetic bispecific antibodies, such as JNJ-78306358, which are designed to recognize the mutant peptide within the HLA groove (ClinicalTrials.gov, NCT04585750). These drugs work by recruiting and activating cytotoxic T-cells to selectively eliminate cells displaying the mutant p53 signature. However, the effectiveness of these therapies can be challenged by the high degree of HLA polymorphism and the potential for tumors to downregulate HLA expression to evade immune detection (Malekzadeh et al., 2019, JCO).

Other names

p53 neoantigen–HLA complexMutant p53–MHC complexp53 mutation-derived neoantigenp53-MHC Class I complexMutant TP53-MHC complex

Redirection of T-cell-mediated cytotoxicity toward tumor cells by specifically binding to the mutant peptide fragment presented within the HLA groove, typically via engineered T-cell receptors (TCRs) or TCR-mimetic antibodies.