Major Histocompatibility Complex-peptide complex (pMHC)

The Major Histocompatibility Complex (MHC) presenting tumor-associated antigen (TAA) peptides, commonly known as the pMHC complex, is a pivotal target in modern oncology and immunotherapy [1]. These complexes are formed when intracellular proteins are degraded by the proteasome into short peptide fragments, which are then loaded onto MHC Class I or II molecules and transported to the cell surface [2]. This mechanism allows the immune system to monitor the internal state of a cell, identifying peptides derived from mutated (neoantigens) or overexpressed (TAAs) proteins that signal malignancy [3]. Therapeutic interventions such as TCR-engineered T cells (TCR-T) and soluble TCR-bispecifics (e.g., Tebentafusp) are designed to recognize these specific peptide-HLA combinations with high sensitivity [1, 4]. Because these targets are highly specific to both the peptide sequence and the patient's HLA genotype, they require precise diagnostic screening for both antigen expression and HLA type [2]. However, the risk of off-target toxicity remains a significant challenge, as seen when therapeutic TCRs cross-react with similar peptides in healthy tissues [5]. Additionally, tumors may evade these therapies by downregulating MHC expression or through the loss of specific HLA alleles [3].

Other names

HLA-peptide complexPeptide-MHC complexTumor-associated antigen-MHC complexMHC-TAA complexAntigen-MHC complex

Recognition by engineered T-cell receptors (TCRs), TCR-bispecifics, or TCR-like antibodies to induce T-cell mediated cytotoxicity against cells presenting specific intracellularly derived peptides [1, 4].