Glypican-3-derived peptide–Major Histocompatibility Complex class I complex (GPC3-pMHC)

Glypican-3 (GPC3) is a cell-surface heparan sulfate proteoglycan that is significantly overexpressed in hepatocellular carcinoma (HCC) and other malignant tumors, such as hepatoblastoma and yolk sac tumors, but has minimal expression in normal adult tissues (Filmus & Capurro, 2013). The GPC3-derived peptide–MHC class I complex represents a specific tumor-associated antigen where intracellularly processed GPC3 peptides are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules, most commonly HLA-A*02:01 or HLA-A*24:02 (Nakatsura et al., 2003). This complex is a critical target for cancer immunotherapy, as it allows the immune system to distinguish malignant cells from healthy ones with high precision. Current therapeutic strategies targeting this complex include TCR-engineered T cells (TCR-T), TCR-like antibodies (also known as TCR-mimic antibodies), and peptide-based vaccines (Sawada et al., 2012). These therapies aim to trigger a potent cytotoxic T-cell response specifically against cells displaying the GPC3-pMHC complex. While promising, the efficacy of these treatments can be limited by the heterogeneity of GPC3 expression, the requirement for specific patient HLA types, and the potential for tumor immune evasion through the downregulation of MHC molecules (Liu et al., 2017).

Other names

GPC3-HLA complexGPC3 peptide-MHC class IGPC3-pHLAGlypican-3-derived peptide–HLA-A*02:01 complexGPC3-MHC-I

The mechanism of action involves the specific recognition of GPC3-derived peptides presented by MHC class I molecules on the tumor cell surface by either engineered T-cell receptors (TCRs) or TCR-mimic antibodies. This recognition triggers the activation of cytotoxic T lymphocytes or the recruitment of immune effector cells, leading to the targeted lysis of GPC3-positive tumor cells (Liu et al., 2017; Sawada et al., 2012).