Tumor-associated antigen-derived peptide–Major Histocompatibility Complex class I (TAA-pMHC-I) (TAA-pMHC-I)

The Tumor-associated antigen-derived peptide–Major Histocompatibility Complex class I (TAA-pMHC-I) complex is a molecular assembly presented on the surface of nucleated cells, serving as a critical interface for immune surveillance (Janeway's Immunobiology). It consists of a short peptide fragment derived from intracellular proteins—such as those overexpressed, mutated, or aberrantly expressed in cancer—bound within the groove of an MHC class I molecule (Nature Reviews Cancer). This complex is specifically recognized by the T-cell receptor (TCR) of CD8+ cytotoxic T cells, which triggers a signaling cascade leading to the destruction of the target cell (PubMed). In oncology, TAA-pMHC-I complexes are highly valued targets because they allow therapeutic agents to address intracellular oncogenic drivers that are otherwise inaccessible to traditional antibody-based therapies (Walseng et al., 2017). Current therapeutic strategies targeting these complexes include TCR-engineered T cells (TCR-T), such as Afamitresgene autoleucel, and soluble TCR-bispecific engagers like Tebentafusp (FDA). These therapies are highly potent but require patients to possess a specific Human Leukocyte Antigen (HLA) allele, such as HLA-A*02:01, to ensure proper binding (NEJM). A significant challenge in targeting TAA-pMHC-I is the risk of off-target toxicity, where the therapeutic TCR may cross-react with similar peptide sequences presented on healthy tissues (Journal of Clinical Oncology). Additionally, tumors may escape detection by downregulating MHC expression or altering antigen processing pathways (Nature).

Other names

pMHC complexHLA-peptide complexAntigen-MHC complexTumor-specific antigen-MHC complexPeptide-HLA complexTAA-pMHC

MHC-restricted T-cell receptor (TCR) binding and redirected T-cell cytotoxicity