Tumor-associated peptide–Major Histocompatibility Complex (pMHC)

Tumor-associated peptide–Major Histocompatibility Complex (pMHC) complexes are the primary molecular structures through which the adaptive immune system identifies and eliminates malignant cells. These complexes consist of a short peptide fragment, typically 8-11 amino acids for MHC Class I, derived from intracellular proteins that are processed and presented on the cell surface (Janeway et al., Immunobiology, 2001). In oncology, these peptides can originate from mutated proteins (neoantigens), cancer-germline antigens, or overexpressed self-antigens, providing a window into the intracellular proteome that is otherwise inaccessible to traditional antibody therapies (Mullins et al., Trends in Immunology, 2022). Therapeutic interventions such as TCR-engineered T cells (TCR-T) and TCR-bispecific engagers like Tebentafusp are designed to recognize specific pMHC combinations with high sensitivity and specificity (Nathan et al., Nature, 2021). By targeting these complexes, drugs can direct potent T-cell mediated cytotoxicity specifically toward tumor cells. However, the clinical application of pMHC-targeted therapies is limited by the requirement for patients to possess specific HLA alleles and the risk of off-target reactivity if the target peptide is shared by proteins in vital healthy organs (Jhunjhunwala et al., Nature Reviews Cancer, 2021).

Other names

HLA-peptide complexTumor-specific antigen-MHC complexNeoantigen-MHC complexPeptide-HLA complexpHLA

Engagement of the peptide-MHC complex by a T-cell receptor (TCR) or TCR-mimetic antibody to trigger T-cell mediated cytotoxicity against the target cell.