Estrogen receptor 1 mutant neoepitope peptides presented on HLA-A*0201 (ESR1-mutant/HLA-A*0201)

Estrogen receptor 1 (ESR1) mutant neoepitope peptides presented on HLA-A*0201 are tumor-specific antigens that arise from somatic mutations in the ESR1 gene, which are frequently observed in patients with metastatic, estrogen receptor-positive breast cancer who have developed resistance to aromatase inhibitors (PubMed: 24185510). These mutations, most commonly Y537S and D538G, result in a modified amino acid sequence that is processed by the proteasome and presented on the cell surface by the HLA-A*0201 molecule (PubMed: 30104253). Because these mutant sequences are not present in the normal human proteome, they serve as highly specific targets for immunotherapy, potentially minimizing damage to healthy tissues that express wild-type ESR1. Current therapeutic strategies targeting this complex include T-cell receptor (TCR) engineered T-cell therapies and personalized neoantigen vaccines designed to elicit a robust cytotoxic T-lymphocyte response (ClinicalTrials.gov: NCT04102436). While promising, the efficacy of targeting these neoepitopes can be challenged by tumor heterogeneity and the potential for the cancer to evade immune detection by downregulating HLA expression (PubMed: 28468935). Overall, this target represents a precision medicine approach to treating endocrine-resistant breast cancer by leveraging the specificity of the adaptive immune system.

Other names

ESR1 neoantigenHLA-A*02:01-restricted ESR1 mutant peptideESR1 Y537S neoepitopeESR1 D538G neoepitopeESR1 mutation-derived neoantigenEstrogen receptor 1 mutation-derived peptide-MHC complex

The mechanism involves the specific recognition of the mutant peptide-HLA complex by the T-cell receptor (TCR) of engineered or endogenous T cells, which triggers the release of cytotoxic granules (perforins and granzymes) to induce apoptosis in the target cancer cell (PubMed: 30104253).