Melanoma-associated Human Leukocyte Antigen–peptide complex (pHLA complex)

Melanoma-associated Human Leukocyte Antigen (HLA)–peptide complexes are specialized molecular structures on the surface of melanoma cells that present intracellular protein fragments to the immune system. These complexes consist of a tumor-associated antigen (TAA) or neoantigen peptide, such as those derived from gp100, MAGE-A4, or NY-ESO-1, nested within the binding groove of an HLA molecule, most commonly HLA-A*02:01 (D'Angelo et al., 2018, Cancer Discovery). They serve as the primary recognition unit for T-cell receptors (TCRs), making them pivotal targets for advanced immunotherapies including TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers like Tebentafusp (Nathan et al., 2021, NEJM). By targeting these complexes, therapies can achieve high specificity for malignant cells, bypassing the limitations of traditional antibody-based approaches that only target surface proteins. However, the clinical utility of targeting pHLA complexes is restricted by the requirement for specific patient HLA types and the risk of "on-target, off-tumor" toxicities if the target peptide is expressed in healthy tissues (Barker & Postel-Vinay, 2023, Nature Reviews Clinical Oncology). Furthermore, tumors may develop resistance by downregulating HLA expression, thereby "hiding" from TCR-mediated detection.

Other names

Melanoma-associated antigen-HLA complexpMHC complexTumor-specific HLA-peptide complexMelanoma neoantigen-MHC complexMHC-peptide complex

Therapeutic agents, such as TCR-engineered T-cells or bispecific TCR molecules, specifically bind to the peptide-HLA complex on the melanoma cell surface, triggering T-cell activation and directed cytotoxicity against the tumor cell (Nathan et al., 2021, NEJM; Hong et al., 2024, The Lancet).