p53 peptide-HLA-A*02:01 complex (p53/HLA-A2)

The p53 peptide presented by HLA-A*02:01 is a peptide-major histocompatibility complex (pMHC) that serves as a specific target for cancer immunotherapy, particularly for tumors harboring TP53 mutations (Hsiue et al., 2021, Science). p53 is a tumor suppressor protein that is frequently mutated or overexpressed in a wide range of human malignancies, including ovarian, colorectal, and lung cancers (Lo et al., 2020, JCI Insight). When p53 is processed by the proteasome, specific peptide fragments are loaded onto HLA-A*02:01 molecules and displayed on the cell surface for recognition by T-cell receptors (TCRs). This complex is particularly significant when it involves common hotspot mutations, such as R175H, which create neoantigens unique to tumor cells. Therapeutic strategies targeting this complex include TCR-engineered T cells (TCR-T) and bispecific antibodies (T-cell engagers) designed to recognize the specific p53 peptide/HLA-A*02:01 interface. These therapies aim to redirect the immune system to selectively eliminate cancer cells while sparing normal tissues that do not present the target at sufficient levels. By binding to the pMHC, these agents facilitate the formation of an immunological synapse and the subsequent release of cytotoxic granules. However, challenges include the extremely low density of pMHC complexes on the cell surface and the potential for off-target reactivity against wild-type p53 peptides in healthy cells (Hsiue et al., 2021, Science). Clinical development focuses on maximizing affinity for the mutant complex while minimizing cross-reactivity with the wild-type version. Overall, it represents a high-precision target for next-generation oncology treatments.

Other names

p53/HLA-A*02:01p53-MHC complexTP53 peptide-HLA-A*02:01p53 R175H/HLA-A2p53(125-134)/HLA-A2

T-cell redirection and activation via TCR-like binding to the peptide-MHC complex, leading to granzyme/perforin-mediated lysis of target cells (Hsiue et al., 2021, Science).