HLA-A*0201 – tyrosinase-derived epitope (HLA-A*0201-Tyr)

The HLA-A*0201 – tyrosinase-derived epitope is a peptide-major histocompatibility complex (pMHC) expressed on the surface of melanocytes and melanoma cells (NIH, 2001). It consists of the HLA-A*0201 class I molecule presenting specific peptides derived from the tyrosinase protein, most notably the immunodominant epitope Tyrosinase 368-376 (YMDGTMSQV), where the asparagine at position 370 is often post-translationally modified to aspartic acid (NIH, 2000; MDPI, 2021). This complex is a key target for cancer immunotherapy because it is recognized by the T-cell receptors (TCRs) of cytotoxic CD8+ T lymphocytes (Frontiers in Immunology, 2021). Therapeutic strategies targeting this pMHC include peptide vaccines, TCR-engineered T-cell (TCR-T) therapies, and TCR-like antibodies (AACR, 2002; MDPI, 2021). However, since tyrosinase is also expressed in normal melanocytes, these therapies can cause on-target/off-tumor toxicities, including vitiligo, uveitis, and hearing loss (Frontiers in Immunology, 2021). Clinical trials have explored various adjuvants and high-affinity TCRs to maximize anti-tumor responses while monitoring for these autoimmune-like side effects (ClinicalTrials.gov, 2021). The target's relevance is primarily in HLA-A*0201-positive patients, who represent a significant portion of the Caucasian population with melanoma (NIH, 2000). Monitoring efficacy often involves tetramer staining to quantify the frequency of T cells specific to this pMHC complex (NIH, 2012).

Other names

HLA-A*02:01-restricted tyrosinase epitopeTyrosinase 368-376 (YMDGTMSQV) / HLA-A*0201 complexTyrosinase 1-9 (MLLAVLYCL) / HLA-A*0201 complexHLA-A2-tyrosinase peptide complexpMHC HLA-A*0201/Tyrosinase

Drugs targeting this complex work by either stimulating endogenous CD8+ T-cell responses (peptide vaccines), providing engineered T cells with specific T-cell receptors (TCR-T), or using bispecific molecules to redirect T cells to the tumor cells presenting the tyrosinase-derived peptide in the context of HLA-A*0201 (NIH, 2001; MDPI, 2021).