T-cell receptor–peptide–major histocompatibility complex class I complex (TCR-pMHC-I)

The T-cell receptor–peptide–major histocompatibility complex class I (TCR-pMHC-I) complex is the fundamental molecular unit for the recognition of malignant cells by the adaptive immune system. This complex forms when an intracellularly processed peptide, often derived from a tumor-associated antigen, is loaded onto a Major Histocompatibility Complex (MHC) class I molecule and presented on the surface of a cancer cell. The specific recognition of this pMHC complex by a cognate T-cell receptor (TCR) on a CD8+ cytotoxic T-lymphocyte triggers a signaling cascade leading to the release of perforins and granzymes, ultimately inducing apoptosis in the target cell. Unlike traditional antibody-based therapies that target surface proteins, TCR-based therapeutics can target the vast array of intracellular proteins that are processed and presented via the MHC pathway. Current therapeutic strategies include TCR-engineered T-cells (TCR-T) and bispecific T-cell engagers like ImmTACs, which are designed to bind specific pMHC complexes with high affinity. However, the efficacy of these treatments is often restricted by the patient's HLA genotype and the potential for off-target toxicity if the targeted peptide sequence is shared by proteins in healthy tissues.

Other names

pMHC-I complexAntigen-MHC class I complexTCR-peptide-HLA complexPeptide-MHC class I complexpMHC class I

Redirection of T-cell cytotoxicity toward tumor cells through the specific recognition of intracellularly derived peptides presented on MHC class I molecules by engineered T-cell receptors or bispecific TCR-based engagers.