Tumor-associated antigen peptide-HLA class I complex (TAA-HLA-I) (TAA-HLA-I)

Tumor-associated antigen (TAA) peptides presented on HLA class I molecules are critical targets for advanced cancer immunotherapies, representing the mechanism by which the immune system surveys the internal proteome of a cell (Rock et al., 2016, PubMed). These complexes consist of short peptide fragments (8-11 amino acids) derived from intracellular proteins—such as mutated neoantigens or overexpressed proteins—that are loaded onto Human Leukocyte Antigen (HLA) class I molecules and displayed on the cell surface (NCI Drug Dictionary). This presentation allows CD8+ cytotoxic T cells to recognize and eliminate cells expressing abnormal proteins via their T-cell receptors (TCRs). Unlike traditional chimeric antigen receptor (CAR) T-cell therapies that target surface proteins, therapies targeting TAA-HLA complexes can address the vast majority of oncogenic drivers that reside within the cell (Nature Reviews Drug Discovery). Current therapeutic modalities include TCR-engineered T cells (TCR-T) and TCR-bispecific engagers, such as the FDA-approved Tebentafusp and Afamitresgene autoleucel (FDA, 2022; FDA, 2024). However, these therapies require precise HLA matching and carry significant risks of off-target toxicity if the targeted peptide sequence is similar to those found in healthy tissues (PubMed). Additionally, tumors may develop resistance through the downregulation of HLA molecules or the loss of the target antigen (StatPearls).

Other names

Tumor-associated antigen peptides presented on HLA class I moleculespMHC-I complexHLA-restricted tumor antigenPeptide-MHC class I complexTumor-specific MHC-peptide complexCancer-testis antigen peptide-HLA complex

Engagement of the peptide-HLA complex by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to induce T-cell mediated cytotoxicity against tumor cells.