Tumor-associated antigen-Human Leukocyte Antigen complex (TAA-HLA complex) (TAA-HLA)

Tumor-associated antigen-Human Leukocyte Antigen (TAA-HLA) complexes represent a critical class of therapeutic targets in oncology, enabling the immune system to detect intracellular oncogenic proteins. These targets are formed when intracellular proteins are processed into short peptide fragments and presented on the cell surface by HLA molecules, primarily Class I (Yuan et al., 2021, Frontiers in Immunology). Unlike traditional monoclonal antibodies that target surface-bound proteins, TAA-HLA complexes allow for the targeting of the vast majority of the proteome, including transcription factors and signaling molecules. Therapeutic strategies leveraging these complexes include T-cell receptor (TCR) engineered T-cells, TCR-bispecific engagers, and cancer vaccines. These therapies are designed to recognize specific peptide-HLA combinations with high affinity and specificity. For example, Tebentafusp targets a gp100 peptide presented by HLA-A*02:01 to treat uveal melanoma (Nathan et al., 2021, NEJM). However, the effectiveness of these treatments is often limited by HLA downregulation in tumors and the requirement for patients to possess specific HLA alleles. Additionally, the risk of off-target toxicity remains a significant concern, as cross-reactivity with similar peptides in healthy tissues can lead to severe adverse events (Hong et al., 2024, The Lancet).

Other names

pHLA complexpMHC complexMHC-presented tumor antigensTumor-specific HLA-peptide epitopesCancer-testis antigen-HLA complexesMHC-peptide complex

Therapeutic agents, such as TCR-engineered T-cells or bispecific TCR-engagers, bind specifically to the TAA-HLA complex, triggering T-cell receptor (TCR) signaling and subsequent T-cell activation. This leads to the release of cytotoxic granules, including perforin and granzymes, which induce apoptosis in the target tumor cell (Nathan et al., 2021, NEJM; Hong et al., 2024, The Lancet).