Tumor antigen-Major Histocompatibility Complex complex (pMHC)

The Tumor antigen-Major Histocompatibility Complex (pMHC) complex is a critical molecular target in cancer immunotherapy, representing the primary interface through which the adaptive immune system identifies malignant cells. These complexes consist of short peptide fragments derived from tumor-specific antigens (TSAs), such as neoantigens from somatic mutations, or tumor-associated antigens (TAAs), such as cancer-testis antigens, which are loaded onto MHC Class I or II molecules and presented on the cell surface. T-cell receptors (TCRs) on cytotoxic T-lymphocytes specifically recognize these pMHC complexes, initiating a signaling cascade that leads to the targeted destruction of the tumor cell. Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, such as the FDA-approved afamitresgene autoleucel, and bispecific T-cell engagers like tebentafusp, which bypasses natural TCR limitations to recruit T-cells to the tumor. Because many of these antigens are derived from intracellular proteins, the pMHC complex allows the immune system to target a much broader range of the proteome than traditional antibody-based therapies. However, the high specificity required for TCR binding poses challenges, as cross-reactivity with self-peptides in healthy organs can lead to severe adverse effects.

Other names

Tumor-specific antigen-MHC complexTumor-associated antigen-MHC complexPeptide-Major Histocompatibility Complex complexNeoantigen-HLA complexCancer-testis antigen-MHC complexpMHC complex

Recognition and binding of the specific peptide-MHC complex by a T-cell receptor (TCR) or TCR-mimetic molecule, which triggers T-cell activation, the release of pro-inflammatory cytokines such as interferon-gamma, and the induction of granzyme- and perforin-mediated apoptosis in the target tumor cell.