Peptide-Human Leukocyte Antigen class I complex (pHLA-I)

Peptide-Human Leukocyte Antigen (HLA) class I complexes (pHLA-I) are the fundamental units of immune recognition on the surface of melanoma cells, consisting of a polymorphic HLA heavy chain, a beta-2 microglobulin light chain, and a short peptide derived from intracellular proteins (UniProt; Janeway's Immunobiology). In melanoma, these complexes present specific tumor-associated antigens (TAAs) such as gp100, MART-1, or NY-ESO-1, as well as neoantigens, to the T-cell receptors (TCRs) of CD8+ cytotoxic T lymphocytes (Garrido et al., 2016, Cancer Immunology, Immunotherapy). This interaction is the primary mechanism by which the adaptive immune system identifies and eliminates malignant cells. Therapeutic strategies targeting these complexes include TCR-engineered T-cell therapies, such as Afamitresgene autoleucel, and bispecific T-cell engagers like Tebentafusp, which are designed to recognize specific pHLA complexes with high affinity to induce potent anti-tumor responses (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, The Lancet). However, challenges such as HLA downregulation as an immune escape mechanism and potential off-target cross-reactivity with similar peptides in healthy tissues remain significant hurdles in clinical development (Jhunjhunwala et al., 2021, Nature Reviews Cancer).

Other names

pMHC-IPeptide-MHC class I complexTumor antigen-HLA complexMHC-I-peptide complexHLA-peptide complex

Engagement of T-cell receptors (TCRs) or TCR-mimetic antibodies to trigger T-cell mediated cytotoxicity against the target cell.