Tumor protein p53 peptide-MHC class I complex (p53-MHC-I) (p53-MHC-I)

The p53 antigen presented on MHC class I of tumor cells is a specialized immunological target consisting of a peptide fragment derived from the tumor suppressor protein p53 bound to a Major Histocompatibility Complex (MHC) class I molecule (Huppa & Davis, 2003). Because p53 is the most frequently mutated gene in human cancers, specific mutations result in the presentation of neoantigens that are absent in healthy tissue, making them ideal targets for precision immunotherapy (Hsiue et al., 2021). Even in cases without mutation, p53 overexpression in tumor cells can lead to a high density of p53-peptide/MHC complexes, which can be exploited as tumor-associated antigens (Zhu et al., 2021). Therapeutic interventions targeting this complex primarily include T-cell receptor (TCR) engineered T-cells and TCR-mimic (TCRm) bispecific antibodies, which are designed to recognize the specific peptide-HLA configuration with high affinity (Lo et al., 2020). These therapies aim to trigger a potent CD8+ T-cell mediated cytotoxic response against malignant cells while sparing normal cells that do not present the target complex at sufficient levels. This approach is particularly valuable because p53 is an intracellular protein, traditionally considered "undruggable" by conventional antibodies; targeting its MHC-presented fragments bypasses this limitation. However, challenges remain, including the requirement for specific HLA genotypes, such as HLA-A*02:01, and the potential for tumors to evade treatment through the loss of MHC expression (Garrido et al., 2016). Clinical trials are currently evaluating TCR-T therapies for patients with specific p53 mutations across various solid tumors (NCT03412877).

Other names

p53-HLA complexp53 pMHCp53-derived peptide-MHC class I complexp53 neoantigen-MHC complex

T-cell redirection and activation via specific recognition of p53-derived peptides presented by MHC class I molecules, leading to granzyme/perforin-mediated lysis of tumor cells.