Human leukocyte antigen A*02:01 (HLA-A*02:01) peptide complex (HLA-A2)

Human leukocyte antigen A*02:01 (HLA-A*02:01) is a polymorphic Major Histocompatibility Complex (MHC) class I molecule responsible for presenting endogenous peptides to CD8+ cytotoxic T lymphocytes (UniProt: P01892). In melanoma, the HLA-A2 peptide-binding groove presents specific tumor-associated antigens (TAAs) such as gp100, MART-1, and tyrosinase, which are recognized as non-self or overexpressed by the immune system (Vigneron, 2015). This pMHC complex is a validated therapeutic target for advanced immunotherapies, most notably Tebentafusp, a bispecific gp100-peptide-HLA-A*02:01-directed T-cell engager approved for uveal melanoma (Nathan et al., 2021, NEJM). Other modalities include TCR-engineered T-cell therapies like Afamitresgene autoleucel, which targets MAGE-A4 peptides in the HLA-A2 context (D'Angelo et al., 2018). The specificity of this target allows for the therapeutic exploitation of intracellular proteins, though it requires patients to be HLA-A*02:01 positive and is susceptible to immune escape through HLA downregulation (Middleton et al., 2002). This target represents a paradigm shift in oncology by moving beyond surface proteins to target the intracellular proteome via the MHC presentation pathway.

Other names

HLA-A*02MHC class I antigen-presenting moleculepMHC complexHLA-A2-peptide grooveHLA-A*02:01

T-cell receptor (TCR) mediated recognition of peptide-MHC complexes, leading to T-cell activation and directed cytotoxicity against tumor cells.