Human leukocyte antigen A*02:01 (HLA-A*02:01) presenting mutant tumor protein p53 (p53) neoantigen peptides (HLA-A*02:01/mutant p53 complex)

The Human leukocyte antigen A*02:01 (HLA-A*02:01) presenting mutant tumor protein p53 (p53) neoantigen peptides complex is a specialized tumor-associated antigen target for cancer immunotherapy. HLA-A*02:01 is a common Class I Major Histocompatibility Complex (MHC) allele that presents intracellularly derived peptides to CD8+ cytotoxic T cells (Hsiue et al., Science 2021). In many malignancies, the TP53 gene acquires hotspot mutations, such as R175H or R248W, which result in the production of neoantigens—peptides with unique amino acid sequences not found in healthy cells (Malekzadeh et al., JCI 2019). These mutant peptides are processed and displayed on the cell surface by HLA-A*02:01, creating a highly specific target for the immune system. Therapeutic strategies like TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (e.g., PC-p53) are designed to recognize this specific peptide-MHC complex, triggering T-cell activation and the selective destruction of tumor cells while sparing normal tissues (Lo et al., JCI 2020). This target is particularly valuable because p53 mutations are ubiquitous across various solid tumors, including ovarian, colorectal, and lung cancers. However, clinical development faces challenges such as potential cross-reactivity with wild-type p53 or other self-peptides and the risk of tumor escape through HLA loss or downregulation (Hsiue et al., Science 2021).

Other names

HLA-A2/p53 mutant complexMHC-I/p53 neoantigen complexHLA-A*02:01-p53R175HHLA-A*02:01-p53R248Wp53-MHC complex

Recognition of the peptide-MHC complex by a T-cell receptor (TCR) or TCR-mimetic antibody, leading to directed T-cell mediated cytotoxicity against the tumor cell (Hsiue et al., Science 2021).