Estrogen receptor 1 (ESR1) mutant neoantigen peptide-MHC complex (ESR1-mutant pMHC)

Estrogen receptor 1 (ESR1) mutant neoantigen peptides presented on MHC complexes are tumor-specific targets arising from somatic mutations in the ESR1 gene, most commonly Y537S and D538G. These mutations occur in approximately 30-40% of metastatic ER-positive breast cancers following aromatase inhibitor therapy (Schiavon et al., 2015, Science Translational Medicine). The mutations result in the presentation of novel peptide sequences on the cell surface via Major Histocompatibility Complex (MHC) molecules, creating neoepitopes that are absent in healthy tissues (Yarchoan et al., 2017, Nature Reviews Cancer). These peptide-MHC (pMHC) complexes are recognized by the immune system as non-self, making them ideal targets for precision immunotherapies such as T-cell receptor (TCR) engineered T cells and neoantigen-based vaccines (Lowery et al., 2019, Science). Therapeutic strategies involve identifying specific TCRs that bind to these mutant ESR1 peptides with high affinity and specificity. This binding directs cytotoxic T cells to eliminate tumor cells while sparing normal cells expressing wild-type ESR1. This target is particularly significant for overcoming endocrine resistance in advanced breast cancer patients (Toy et al., 2013, Nature Genetics). Clinical development focuses on matching the specific ESR1 mutation with the patient's HLA type, such as HLA-A*02:01, to ensure effective antigen presentation. Monitoring of these targets often involves liquid biopsies to detect circulating tumor DNA (ctDNA) harboring the relevant mutations. Overall, ESR1-mutant pMHC complexes represent a promising frontier in the personalized treatment of refractory breast cancer.

Other names

ESR1 mutation-derived neoantigensESR1-mutant HLA-restricted peptidesEstrogen receptor alpha mutant neoepitopesESR1-mutant pMHCESR1 neoepitopes

Recognition of the mutant peptide-MHC complex by T-cell receptors (TCRs) leads to T-cell activation and targeted lysis of tumor cells (Lowery et al., 2019, Science).