Lipoxygenase homology domain-containing protein 1-derived peptide–HLA-A*02:01 complex (LOXHD1–HLA-A*02:01)

The Lipoxygenase homology domain-containing protein 1 (LOXHD1)-derived peptide–HLA-A*02:01 complex is a specialized peptide-major histocompatibility complex (pMHC) that serves as a target for cancer immunotherapy, particularly in acute myeloid leukemia (AML). LOXHD1 is a protein primarily known for its role in the mechanotransduction of hair cells in the inner ear, where mutations are linked to hereditary hearing loss (DFNB77) (UniProt Q8IVV2; Grati et al., 2015). However, recent research has identified LOXHD1 as a tumor-associated antigen that is overexpressed in leukemic stem cells and blasts while maintaining low expression in most healthy tissues (Waltemathe et al., 2020, Blood). The complex is formed when specific intracellularly processed peptides from LOXHD1, such as the decamer VLLGPGRPYV, are loaded onto the HLA-A*02:01 molecule and presented on the cell surface. This pMHC complex is recognized by the T-cell receptors (TCRs) of cytotoxic T lymphocytes, making it a candidate for TCR-engineered T-cell (TCR-T) therapies and peptide vaccines. Therapeutic strategies targeting this complex aim to induce a selective immune response against malignant cells, though potential on-target, off-tumor toxicity involving the inner ear remains a critical safety consideration during clinical development.

Other names

LOXHD1-pMHCLOXHD1-HLA-A2 complexLOXHD1_455-HLA-A*02:01VLLGPGRPYV-HLA-A*02:01

T-cell receptor (TCR) recognition of the peptide-MHC complex leads to the activation of cytotoxic T lymphocytes and subsequent lysis of the target cell.