Major histocompatibility complex class I-melanoma-associated antigen peptide complex (pMHC-I) (pMHC-I)

Major histocompatibility complex (MHC) class I molecules (HLA-A, -B, and -C) are cell surface glycoproteins that play a fundamental role in the adaptive immune system by presenting intracellularly derived peptides to CD8+ cytotoxic T cells (1.1.1, 1.6.5). In melanoma, these molecules present peptides derived from melanoma-associated antigens (MAAs) like gp100, MART-1, and the MAGE family (1.2.1, 1.4.1). These peptide-MHC (pMHC) complexes serve as highly specific flags for the immune system to identify and eliminate malignant cells (1.1.4, 1.6.2). Therapeutic strategies targeting these complexes include bispecific T-cell engagers, TCR-engineered T-cell therapies (TCR-T), and cancer vaccines (1.3.2, 1.4.5, 1.6.3). Because these targets represent fragments of intracellular proteins, they expand the druggable proteome beyond traditional cell-surface proteins (1.3.2, 1.6.2). Tebentafusp is a notable approved therapy that redirects T cells to the gp100 peptide presented by HLA-A*02:01 (1.3.4). However, clinical development faces challenges such as potential cross-reactivity with similar peptides in vital organs like the heart or brain (1.5.1, 1.6.2). Additionally, tumors may downregulate MHC expression or lose specific HLA alleles to evade immune detection (1.2.3). Patient selection typically requires both the presence of a specific HLA genotype and the expression of the target antigen (1.3.4). Overall, targeting these complexes represents a sophisticated approach to precision oncology and immunotherapy (1.6.5).

Other names

Peptide-MHC class I complexPeptide-HLA class I complexMelanoma-associated antigen-MHC complexTumor-specific MHC-peptide complexpHLA complex

T-cell redirection via bispecific T-cell engagers, adoptive T-cell transfer using TCR-engineered T cells (TCR-T), active immunization with peptide vaccines, and TCR-like antibody-mediated cytotoxicity.