Tumor protein p53 antigen presented on MHC class I (p53-MHC-I)

Tumor protein p53 (TP53) is a master tumor suppressor and the most frequently mutated gene in human cancers, with mutations often leading to the stable overexpression of mutant p53 protein (Hsiue et al., Science, 2021). Although p53 is an intracellular protein and traditionally considered undruggable by antibodies, it is processed by the proteasome into short peptides that are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules (Lo et al., JCI, 2020). This p53-MHC-I complex acts as a neoantigen or tumor-associated antigen, providing a unique molecular signature for immune recognition of malignant cells. Therapeutic targeting of the p53-MHC-I complex involves the use of T-cell receptor (TCR)-engineered T cells (TCR-T) or TCR-like bispecific antibodies that can bind the peptide-MHC complex with high specificity (Deniger et al., Nature, 2018). These approaches are typically restricted to specific HLA alleles, most commonly HLA-A*02:01, and specific p53 hotspot mutations such as R175H. While promising for treating a wide range of solid tumors, the efficacy of these therapies can be limited by the loss of MHC expression in advanced cancers and the potential for off-target reactivity against wild-type p53 sequences (Malekzadeh et al., JCI, 2019).

Other names

p53-HLA complexp53 peptide-MHC complexp53 neoantigenp53-MHC-I complexMutant p53-HLA-A2 complex

Redirection of T-cell cytotoxicity toward cancer cells by specifically binding to mutant p53 peptides presented by MHC class I molecules on the cell surface.