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

Tumor-associated antigen peptide–Major Histocompatibility Complex class I (TAA-pMHC-I) complexes are the fundamental units recognized by the cellular immune system to distinguish malignant cells from healthy ones (Hassan et al., JCI, 2020). These complexes are formed when intracellular proteins are degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto MHC class I molecules (Rock et al., Trends in Immunology, 2016). Once displayed on the cell surface, these complexes serve as ligands for T-cell receptors (TCRs) found on CD8+ cytotoxic T-lymphocytes. In oncology, therapeutic targeting of these complexes allows for the recognition of intracellular tumor-specific or tumor-associated antigens that are otherwise inaccessible to conventional monoclonal antibodies (Koneru et al., Journal of Hematology & Oncology, 2021). Modern therapeutic modalities, such as TCR-engineered T-cells (TCR-T) and Immune Mobilizing Monoclonal TCRs Against Cancer (ImmTACs), are designed to bind these complexes with high affinity and specificity. For example, the drug Tebentafusp targets a gp100-derived peptide presented by HLA-A*02:01 to treat uveal melanoma (Nathan et al., NEJM, 2021). A significant challenge in this field is the requirement for specific HLA genotypes in patients, as the drug must match the patient's MHC allele to function. Additionally, tumors may escape detection by downregulating MHC expression or through the loss of heterozygosity in HLA genes (McGranahan et al., Cell, 2017). Safety concerns primarily involve off-target toxicity, where the therapeutic TCR might cross-react with similar peptides presented on healthy tissues (Linette et al., Blood, 2013).

Other names

pMHCpHLAPeptide-HLA complexTumor-specific peptide-MHCMHC-I-peptide complexAntigen-MHC complex

Targeting of TAA-pMHC-I complexes is achieved through engineered T-cell receptors (TCRs) or TCR-mimetic antibodies that recognize the specific peptide-MHC combination. This interaction facilitates the formation of an immunological synapse, leading to the release of perforins and granzymes by T-cells, which induces apoptosis in the target tumor cell. Bispecific molecules like ImmTACs function by redirecting non-specific T-cells to the tumor via a CD3-binding domain, while TCR-T therapies utilize patient-derived T-cells genetically modified to express a high-affinity TCR specific for the pMHC complex.