Tumor antigen-Major Histocompatibility Complex (pMHC)

Tumor antigen-Major Histocompatibility Complex (pMHC) refers to the molecular assembly of a short peptide fragment, derived from a tumor-specific or tumor-associated protein, bound to a Major Histocompatibility Complex (MHC) molecule (HLA in humans) on the surface of a cancer cell. These complexes are the fundamental targets recognized by the T-cell receptors (TCRs) of both naive and mature T-cells, serving as the primary signal for the adaptive immune system to identify and eliminate malignant cells (Nature Reviews Immunology, 2021). Unlike traditional monoclonal antibodies that are limited to targeting surface-expressed proteins, pMHC-targeting therapies can access the intracellular proteome, including oncogenic drivers and neoantigens that are processed and presented as peptides. In clinical practice, these complexes are targeted by advanced modalities such as TCR-engineered T-cell therapies (e.g., Afamitresgene autoleucel) and TCR-bispecific engagers (e.g., Tebentafusp), which bypass the need for endogenous T-cell recognition (The Lancet, 2024; NEJM, 2021). The therapeutic efficacy of targeting pMHCs is strictly dependent on the patient's specific HLA haplotype and the density of the peptide-MHC complex on the tumor surface. A major challenge in this field is the risk of severe off-target toxicity, as engineered TCRs may cross-react with similar peptide sequences presented on healthy tissues, necessitating rigorous preclinical screening for safety (Science Translational Medicine, 2013).

Other names

Peptide-MHC complexTumor-associated antigen-MHC complexNeoantigen-MHC complexHLA-peptide complexpMHC complex

Drugs targeting these complexes, such as TCR-engineered T-cells (TCR-T) or bispecific T-cell engagers (BiTEs), utilize a T-cell receptor (TCR) or TCR-like binding domain to specifically recognize a peptide fragment presented by an MHC molecule on the tumor cell surface. This binding event triggers T-cell activation, leading to the release of perforins and granzymes that induce apoptosis in the target cancer cell (Nature Reviews Cancer, 2021; NEJM, 2021).