HLA-A*02:01 peptide-binding groove presenting MART-1, gp100, and tyrosinase epitopes (HLA-A*02:01/MAA-pMHC)

HLA-A*02:01 is a highly prevalent Class I Major Histocompatibility Complex (MHC) allele that plays a central role in the cellular immune response by presenting endogenous peptides to CD8+ T cells (UniProt P01892). In melanoma, the peptide-binding groove of HLA-A*02:01 frequently presents epitopes derived from melanocyte differentiation antigens, specifically MART-1 (UniProt Q16655), gp100 (UniProt P40967), and tyrosinase (UniProt P14679). These peptide-MHC (pMHC) complexes are recognized as "non-self" or "altered-self" by the immune system, making them prime targets for cancer immunotherapy. Therapeutic interventions, such as T-cell receptor (TCR) engineered T-cells and bispecific T-cell engagers like tebentafusp, are designed to bind these specific pMHC complexes to trigger tumor cell lysis (Nathan et al., NEJM 2021). However, because these antigens are also expressed in healthy melanocytes in the skin, eye, and ear, targeting them can result in on-target, off-tumor toxicities such as vitiligo and uveitis.

Other names

HLA-A2/MART-1/gp100/Tyrosinase complexMHC-peptide complexMelanoma-associated antigen-presenting HLA-A*02:01HLA-A*02:01/Melan-A/PMEL/TYR complex

T-cell receptor (TCR) mediated recognition and subsequent cytotoxic T-lymphocyte (CTL) activation