p53-derived HLA-A*02:01-restricted peptide-MHC complex (p53/HLA-A2 pMHC)

The p53-derived HLA-A*02:01-restricted peptide-MHC complex is a specialized immunotherapy target consisting of short peptide fragments from the tumor suppressor protein p53 presented by the Human Leukocyte Antigen A2 (HLA-A2) molecule (Hsiue et al., 2021, Science). In many malignancies, the TP53 gene is either overexpressed or carries specific 'hotspot' mutations, leading to the presentation of these peptides on the cell surface via the MHC class I pathway (Lo et al., 2020, JCI). This complex acts as a neoantigen or tumor-associated antigen that can be recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T lymphocytes. Therapeutic strategies targeting this complex include TCR-engineered T cells (TCR-T), bispecific T-cell engagers (BiTEs) like PC1, and TCR-like antibodies that mimic the specificity of natural immune recognition (Malekzadeh et al., 2019, Frontiers in Immunology). Because p53 is an intracellular protein, the pMHC complex is the primary mechanism for the immune system to detect its status, making it a high-value target for precision oncology. However, clinical application is restricted to patients with the HLA-A*02:01 allele and is subject to challenges such as MHC downregulation by tumors to evade immune detection.

Other names

p53-HLA-A2 complexp53 peptide-MHC class I complexp53-derived T-cell epitopep53 neoantigen-MHC complexp53-HLA-A*02:01

Redirection of T-cell mediated cytotoxicity toward tumor cells through the specific recognition of p53-derived peptides presented on HLA-A2 by engineered T-cell receptors (TCRs) or TCR-like antibodies.