Mutant tumor protein p53 peptide–Human leukocyte antigen class I complex (Mutant TP53–HLA-I complex)

Mutant TP53 peptide–HLA class I complexes are highly specific tumor neoantigens presented on the surface of cancer cells. They are formed when the mutated tumor protein p53 (TP53), a common driver of oncogenesis, is degraded by the proteasome into short peptides that are subsequently loaded onto Human Leukocyte Antigen (HLA) class I molecules for presentation to the immune system (Hsiue et al., Science, 2021). Because these specific peptide-HLA combinations are unique to malignant cells harboring TP53 mutations and are absent in healthy tissues, they serve as ideal targets for precision immunotherapies, including T-cell receptor (TCR) engineered T-cells and bispecific antibodies (Hsiue et al., Science, 2021; PubMed: 33649166). Therapeutic development often focuses on "hotspot" mutations, such as R175H, presented by common HLA alleles like HLA-A*02:01, to treat a broad range of solid tumors (ClinicalTrials.gov: NCT05113602). While these complexes offer high tumor specificity, challenges remain regarding the low density of the complexes on the cell surface and the potential for tumor escape through the loss of HLA expression (Vogelstein et al., Science, 2013).

Other names

p53 neoantigen-HLA complexMutant p53-MHC class I complexTP53 mutation-derived neoepitope-HLA complexp53 R175H-HLA-A*02:01 complexMutant p53-HLA-A2 complex

T-cell receptor (TCR) binding, Bispecific T-cell engager (BiTE) mediated T-cell redirection, Antibody-dependent cellular cytotoxicity (ADCC), MHC-restricted T-cell lysis