Tumor protein p53 R175H mutant peptide–HLA-A*02:01 complex (p53 R175H–HLA-A*02:01)

The p53 R175H peptide–HLA-A*02:01 complex is a tumor-specific neoantigen consisting of a mutated fragment of the tumor protein p53 (TP53) presented by the Human Leukocyte Antigen (HLA) allele A*02:01 (Hsiue et al., Science, 2021). The R175H mutation is a common hotspot mutation that occurs in approximately 5% of all cancers, including high-grade serous ovarian cancer and colorectal cancer (Lo et al., JCI, 2020). In malignant cells, this mutation leads to the stabilization and accumulation of p53, resulting in the presentation of the R175H-derived peptide on the cell surface via MHC Class I molecules (Hsiue et al., Science, 2021). This complex is a highly attractive therapeutic target because it is absent in normal tissues, which express only wild-type p53 at low levels (Vogelstein et al., Nature, 2000). Current therapeutic strategies include bispecific T-cell engagers, such as H2-scDb, and T-cell receptor (TCR) engineered T-cells designed to recognize the specific peptide-HLA interface (Hsiue et al., Science, 2021; Lo et al., JCI, 2020). These therapies aim to redirect the immune system to selectively kill cancer cells while sparing healthy cells that do not present this specific neoantigen.

Other names

p53 R175H/HLA-A2p53 R175H neoantigenMutant p53-HLA-A*02:01 complexp53 R175H-A2

T-cell redirection and activation through specific binding of the T-cell receptor or a bispecific antibody to the mutant peptide-HLA complex, leading to granzyme/perforin-mediated lysis of the target cell (Hsiue et al., Science, 2021).