p53 R175H mutant peptide-HLA-A*02:01 complex (p53-R175H/HLA-A*02:01)

The p53 R175H mutant peptide presented by HLA-A*02:01 is a tumor-specific neoantigen complex. The TP53 gene is the most frequently mutated gene in human cancer, and the R175H substitution is a prominent hotspot mutation that leads to loss of tumor suppressor function and gain of oncogenic properties (Hsiue et al., 2021, Science). Intracellular mutant p53 proteins are processed by the proteasome into peptides, including the 10-amino acid sequence HMTEVVRHC, which is then presented on the cell surface by the Human Leukocyte Antigen (HLA) allele A*02:01 (Lo et al., 2020, JCI). This complex is a prime target for immunotherapy because it is expressed exclusively by cancer cells and not by healthy tissues, which present wild-type p53 peptides that do not bind HLA-A*02:01 with the same affinity. Therapeutic approaches targeting this complex include bispecific T-cell engagers (BiTEs) and TCR-engineered T cells (TCR-T), which aim to overcome the challenge of low antigen density on the cell surface (Hsiue et al., 2021, Science). Clinical development focuses on patients with solid tumors who possess both the specific TP53 mutation and the HLA-A*02:01 haplotype.

Other names

p53 R175H neoantigenp53 R175H-HLA-A*02:01Mutant p53 R175H peptide-MHC complexp53 R175H/A2HMTEVVRHC-HLA-A*02:01 complex

Redirection of T-cell cytotoxicity toward cancer cells through specific recognition of the mutant peptide-MHC complex by bispecific antibodies or engineered T-cell receptors (TCRs) (Hsiue et al., 2021, Science).