Tumor antigen presented by major histocompatibility complex molecule (pMHC)

A tumor antigen presented by a major histocompatibility complex (MHC) molecule, commonly referred to as a peptide-MHC (pMHC) complex, is a fundamental target in modern cancer immunotherapy. These complexes consist of a short peptide fragment, derived from intracellular tumor-specific or tumor-associated proteins, which is loaded onto MHC Class I or II molecules (Human Leukocyte Antigens or HLA in humans) and displayed on the cell surface [NCBI Bookshelf, 2023]. This presentation mechanism allows the immune system to monitor the internal proteome of a cell, enabling T-cells to recognize and eliminate malignant cells via their T-cell receptors (TCRs). Therapeutic strategies targeting pMHC complexes include TCR-engineered T-cell (TCR-T) therapies, such as Afamitresgene autoleucel, and bispecific TCR-based engagers like Tebentafusp [FDA, 2024; Immunocore, 2022]. By targeting the pMHC rather than surface proteins, these therapies can address a much wider range of oncogenic drivers, including those that are traditionally considered undruggable. However, the clinical application of these therapies requires precise HLA matching and carries risks of severe off-target toxicities if the targeted peptide sequence is shared by proteins in vital healthy organs [Journal of Hematology & Oncology, 2021].

Other names

Peptide-major histocompatibility complexpMHC complexHLA-peptide complexTumor-associated antigen-MHC complexNeoantigen-MHC complexMHC-restricted tumor antigen

Therapeutic agents target these complexes through engineered T-cell receptors (TCR-T), TCR-like antibodies, or bispecific T-cell engagers (ImmTACs) that bind specifically to the peptide-MHC interface, triggering cytotoxic T-lymphocyte (CTL) mediated lysis of the tumor cell [Nature Reviews Drug Discovery, 2021].