Peptide-Major Histocompatibility Complex Class I (pMHC-I) (pMHC-I)

Peptide-Major Histocompatibility Complex Class I (pMHC-I) complexes are cell-surface structures essential for the adaptive immune system's surveillance of the intracellular proteome [2, 14]. These complexes consist of a polymorphic HLA class I heavy chain, a beta-2 microglobulin subunit, and a short peptide (typically 8-11 amino acids) derived from the degradation of endogenous proteins [16, 24]. In oncology, pMHC-I complexes present tumor-associated antigens (TAAs) or neoantigens, which serve as highly specific markers for malignant cells [23, 25]. Because they present fragments of intracellular proteins, they allow the immune system to "see" inside the cell, expanding the targetable landscape beyond traditional surface proteins [8, 16]. Therapeutic strategies targeting pMHC-I include TCR-engineered T cells (TCR-T) and bispecific T-cell engagers like ImmTACs, which provide high-affinity recognition of specific peptide-HLA combinations [6, 13, 17]. A significant challenge in targeting these complexes is the requirement for patient-specific HLA matching (HLA restriction) and the risk of off-target toxicity if the targeted peptide sequence is shared with proteins in healthy tissues [2, 23]. Additionally, tumors frequently employ immune evasion tactics such as the downregulation of MHC-I expression or the loss of specific HLA alleles to avoid detection [1, 4, 11]. Despite these challenges, pMHC-I targeting represents a cornerstone of precision immunotherapy, enabling the selective destruction of cancer cells based on their unique genetic and proteomic signatures [9, 27].

Other names

Patient-specific peptide-MHC complexes presenting tumor-associated antigens or neoantigens on HLA class IpMHC class IHLA-peptide complexpHLA complexNeoantigen-HLA complexTumor-associated antigen-HLA complexpMHC-I

Drugs targeting pMHC-I complexes utilize engineered T-cell receptors (TCRs) or TCR-mimic antibodies to specifically recognize and bind the peptide-HLA complex on the cell surface. This binding event redirects T-cell cytotoxicity toward the target cell, either through adoptive transfer of TCR-engineered T cells (TCR-T) or via bispecific molecules (e.g., ImmTACs) that bridge the pMHC-I on the tumor with CD3 on endogenous T cells.