Mucin 1 signal peptide (MUC1-SP)

Mucin 1 (MUC1) is a transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in over 90% of breast, ovarian, and pancreatic cancers [UniProt P15941]. The MUC1 signal peptide domain consists of the N-terminal 20 amino acids that direct the protein to the endoplasmic reticulum [PubMed: 26861459]. In cancer cells, fragments of this signal peptide are processed and presented on the cell surface by HLA-A*02:01 molecules, serving as a tumor-associated antigen [PubMed: 11160694]. This makes the MUC1 signal peptide a unique target for TCR-engineered T-cell therapies, which can specifically recognize this peptide-HLA complex to induce tumor cell lysis [Alaunos Therapeutics]. Because the signal peptide is not glycosylated, it avoids the masking effects of the heavily O-glycosylated extracellular tandem repeat domain of MUC1, providing a more accessible epitope for immune recognition [PubMed: 22490281]. Targeting this domain allows for the destruction of MUC1-positive tumor cells while potentially minimizing impact on normal tissues where MUC1 processing or HLA presentation of this specific peptide may differ. Clinical development of therapies targeting this domain focuses on patients who are both MUC1-positive and HLA-A*02:01-positive.

Other names

MUC1 signal sequenceCD227 signal peptideEpisialin signal peptideMUC-1/SPMucin-1 leader sequence

Engineered T-cell receptors (TCRs) recognize the MUC1 signal peptide fragment presented by HLA-A*02:01 on the surface of tumor cells, leading to T-cell activation and tumor cell lysis.