Patient-specific peptide-major histocompatibility complex (pMHC)

The patient-specific peptide-major histocompatibility complex (pMHC) is a molecular assembly on the surface of tumor cells consisting of a degraded protein fragment (peptide) bound to a Major Histocompatibility Complex (MHC) molecule, specifically Human Leukocyte Antigen (HLA) in humans. In oncology, these peptides often represent neoantigens derived from somatic mutations unique to an individual patient's tumor, making the pMHC a highly specific target for immunotherapy (Nature Reviews Drug Discovery, 2021). The primary biological function of the pMHC is to present intracellular antigens to the adaptive immune system, acting as the specific ligand for T-cell receptors (TCRs) on CD8+ cytotoxic T lymphocytes (Frontiers in Immunology, 2020). Recognition of the pMHC by a cognate TCR triggers T-cell activation, proliferation, and the subsequent release of cytotoxic granules to kill the target cell. Therapeutic strategies leveraging this target include personalized neoantigen vaccines, such as mRNA-4157, which stimulate the expansion of endogenous neoantigen-specific T cells, and adoptive cell therapies like TCR-engineered T cells (TCR-T) that are pre-programmed to recognize specific pMHC epitopes (Nature, 2023; Journal of Hematology & Oncology, 2022). A significant challenge in targeting pMHCs is the potential for tumor escape through the downregulation of MHC expression or the loss of specific HLA alleles, which renders the tumor invisible to T-cell recognition (Cancer Discovery, 2019).

Other names

Neoantigen-MHC complexTumor-specific peptide-MHCHLA-peptide complexNeoepitope-HLA complexpMHC complex

Recognition by T-cell receptors (TCRs) or TCR-like antibodies to induce T-cell mediated lysis of tumor cells.