Tumor-associated antigen–derived peptides presented on Human Leukocyte Antigen class I (TAA-HLA-I complex)

Tumor-associated antigen (TAA)-derived peptides presented on Human Leukocyte Antigen (HLA) class I molecules are essential targets for modern cancer immunotherapy, enabling the immune system to detect intracellular oncogenic proteins (PubMed: 30103341). These targets are formed when intracellular proteins are degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto HLA class I molecules for surface display (Nature Reviews Cancer: 10.1038/nrc3803). This mechanism allows CD8+ cytotoxic T cells to recognize and eliminate tumor cells through their T-cell receptors (TCRs). Therapeutic interventions such as TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers, like Tebentafusp, specifically bind these peptide-HLA complexes to trigger a potent anti-tumor response (NEJM: 10.1056/NEJMoa2103483). A significant challenge in targeting these complexes is the requirement for specific HLA alleles in patients, such as HLA-A*02:01, and the potential for tumor immune escape through HLA downregulation or loss (Frontiers in Immunology: 10.3389/fimmu.2020.01260).

Other names

Peptide-HLA class I complexpHLA-IMHC class I-restricted tumor antigensTumor-associated antigen-MHC complexpMHCTumor-specific antigen-HLA complex

Therapeutic agents targeting these complexes, such as TCR-engineered T-cells (TCR-T) or bispecific T-cell engagers (ImmTACs), utilize high-affinity T-cell receptors or TCR-like antibodies to specifically recognize the peptide-HLA combination on the tumor cell surface. This binding facilitates the formation of an immunological synapse, leading to the release of perforins and granzymes by T-cells and subsequent osmotic lysis and apoptosis of the target tumor cell (PubMed: 34551227; Nature Reviews Cancer: 10.1038/nrc3803).