Melanoma-associated peptide-HLA class I complex (pHLA-I)

Melanoma-associated peptide-HLA class I complexes are molecular assemblies consisting of a melanoma-specific peptide fragment bound to a Human Leukocyte Antigen (HLA) class I molecule (Sherman et al., 2019, PMC6517554). These complexes are presented on the surface of melanoma cells and serve as the primary recognition signal for CD8+ cytotoxic T cells via their T-cell receptors (TCRs). Common peptides involved in these complexes are derived from proteins such as gp100, MART-1, MAGE-A4, and NY-ESO-1, typically presented by the HLA-A*02:01 allele (D'Angelo et al., 2018, Cancer Discovery). Therapeutic strategies targeting these complexes include TCR-engineered T-cell therapies (TCR-T) and bispecific T-cell engagers, such as Tebentafusp, which was the first TCR-based therapy approved for metastatic uveal melanoma (Nathan et al., 2021, NEJM). Because these targets are highly specific to the intracellular proteome of the cancer cell, they allow for the targeting of antigens that are not accessible by traditional antibody-based therapies. The clinical success of these therapies depends heavily on the patient's HLA genotype and the expression level of the specific melanoma antigen (Merchant et al., 2024, Lancet Oncology). Safety concerns often involve off-target effects on healthy tissues that may express similar peptides, such as melanocytes in the skin or eye, as well as systemic inflammatory responses like cytokine release syndrome.

Other names

Melanoma antigen-HLA complexpMHC class I complexPeptide-MHC complexTumor-associated antigen-HLA complexMelanoma peptide-MHC complexpMHC

These complexes are targeted by T-cell receptor (TCR) based therapeutics, including TCR-engineered T cells (TCR-T) and bispecific T-cell engagers (ImmTACs). These drugs bind specifically to the peptide-HLA complex on the tumor cell surface and either provide an engineered T cell to attack the tumor or bridge endogenous T cells to the tumor cell, leading to directed cytotoxicity (Nathan et al., 2021, NEJM; Merchant et al., 2024, Lancet Oncology).