Mucin 1-derived peptide–Major Histocompatibility Complex (MUC1-peptide–MHC)

The Mucin 1 (MUC1)-derived peptide–Major Histocompatibility Complex (MHC) is a specific molecular target formed when intracellularly processed fragments of the MUC1 protein are presented on the cell surface by MHC Class I molecules, most commonly HLA-A*02:01 (PubMed: 26903321). MUC1 is a heavily O-glycosylated transmembrane protein that is significantly overexpressed and loses its apical polarization in many adenocarcinomas, including those of the breast, pancreas, and lung (UniProt: P15941). In malignant cells, the aberrant processing of MUC1 leads to the presentation of specific peptides that can be recognized by the cellular immune system. This complex is a primary focus for "TCR-like" or "TCR-mimetic" antibodies and chimeric antigen receptor (CAR) T-cell therapies, such as ET1402L1, which are engineered to bind the peptide-MHC assembly with high specificity (PubMed: 30104343). By targeting the pMHC rather than the native, bulky MUC1 glycoprotein, these therapies can bypass the shielding effect of heavy glycosylation and target the tumor at the sequence level. However, the clinical application of such therapies is restricted to patients with matching HLA haplotypes and faces challenges regarding the density of antigen presentation and potential off-target effects on normal epithelial tissues (ClinicalTrials.gov: NCT04025216).

Other names

MUC1-pMHCMUC1-HLA complexMUC1-derived peptide presented by HLA-A2MUC1-HLA-A*02:01 complexMucin 1-derived peptide–MHC class I complex

T-cell receptor (TCR) mimicry, CAR-T cell mediated lysis, Vaccine-induced T-cell activation, TCR-T cell recognition