Mesothelin peptide-MHC class I complex (MSLN-pMHC)

Mesothelin (MSLN) is a 40 kDa glycosylphosphatidylinositol-anchored glycoprotein that is highly overexpressed in several aggressive malignancies, including malignant mesothelioma, ovarian cancer, and pancreatic adenocarcinoma (Hassan et al., 2004, PMID: 15150553). While MSLN is a well-validated target for antibody-drug conjugates and CAR-T cells, the mesothelin-derived peptide presented by MHC class I molecules (specifically HLA-A*02:01) represents a specialized target for T-cell receptor (TCR)-based therapies. The most prominent epitope, MSLN 542–550 (SLLMWITQC), is processed intracellularly and presented on the cell surface, allowing for recognition by TCR-engineered T cells or TCR-like CAR-T cells such as ET1402L1 (He et al., 2017, PMID: 28115591). This approach expands the targetable landscape of MSLN by utilizing the high sensitivity of the TCR to detect low-density pMHC complexes (Tang et al., 2013, PMID: 23408348). Clinical utility is limited to patients expressing the specific HLA-A*02:01 allele, necessitating companion diagnostic testing. Safety considerations include potential on-target off-tumor effects on normal mesothelial tissues and systemic inflammatory responses like cytokine release syndrome.

Other names

Mesothelin-derived peptide-HLA complexMSLN-HLA-A*02:01 complexMesothelin epitope-MHC complexMSLN 542-550 peptide-MHC

Recognition of the MSLN peptide-MHC complex by engineered T-cell receptors (TCRs) or TCR-like antibodies, triggering T-cell activation, cytokine release, and cytotoxic lysis of the target tumor cell.