Mutant tumor protein p53 peptides presented by human leukocyte antigen class I (Mutant TP53-HLA-I)

Mutant tumor protein p53 (TP53) peptides presented by human leukocyte antigen (HLA) class I molecules are a prominent class of cancer neoantigens. TP53 is the most frequently mutated gene in human oncology, with specific hotspot mutations (such as R175H, R248Q, and R273H) occurring across various solid tumors including ovarian, colorectal, and lung cancers (Hsiue et al., 2021, Science). These mutations often result in the stabilization and accumulation of the mutant p53 protein, which is subsequently degraded by the proteasome into peptides that are loaded onto HLA class I molecules for surface presentation. Because these specific mutant peptide-HLA complexes are absent in healthy tissues, they provide a highly selective target for immunotherapeutic interventions such as T-cell receptor (TCR) engineered T-cells and bispecific antibodies (Lo et al., 2019, JCI). Therapeutic strategies targeting these complexes aim to induce a potent, mutation-specific cytotoxic T-cell response to eradicate tumor cells while sparing normal cells that express only wild-type p53 at low levels. Clinical development focuses on matching specific p53 mutations with specific HLA alleles, such as the R175H mutation presented by HLA-A*02:01. This target represents a significant opportunity for off-the-shelf neoantigen therapy due to the high prevalence of hotspot mutations across the patient population.

Other names

Mutant p53 neoantigensp53-HLA-I complexTP53 mutation-derived neoepitopesp53-MHC class I complex

Engagement of the mutant peptide-HLA complex by engineered T-cell receptors (TCRs) or TCR-like antibodies to trigger T-cell mediated lysis of tumor cells.