Tumor-associated antigen peptide–HLA-A*02 complex (TAA-HLA-A*02)

The Tumor-associated antigen peptide–HLA-A*02 complex is a molecular assembly on the surface of cancer cells that serves as a critical recognition unit for the adaptive immune system [Nathan et al., 2021, NEJM; Merchant et al., 2024, Lancet]. It consists of a processed peptide fragment, typically 8-11 amino acids long, derived from an intracellular tumor-associated antigen (TAA) such as MAGE-A4, NY-ESO-1, or gp100, nested within the binding groove of the Human Leukocyte Antigen (HLA) A*02:01 molecule [Gonzalez-Galarza et al., 2020, Nucleic Acids Res; D'Angelo et al., 2018, Cancer Discovery]. Because HLA-A*02 is highly prevalent in many human populations, it is a primary target for the development of T-cell receptor (TCR)-based therapies [Gonzalez-Galarza et al., 2020, Nucleic Acids Res]. These therapies, including TCR-engineered T-cells (TCR-T) and TCR-bispecific engagers, are designed to bypass the limitations of traditional antibodies by targeting intracellular proteins presented as pMHC complexes [Nathan et al., 2021, NEJM; Adaptimmune, 2024, Press Release]. Upon binding, these therapeutic agents recruit and activate cytotoxic T-lymphocytes to induce apoptosis in the target tumor cell [Merchant et al., 2024, Lancet]. This approach is particularly valuable in treating solid tumors where surface-expressed antigens are scarce. However, the success of these treatments depends on the high-affinity recognition of the specific peptide-HLA combination and the avoidance of cross-reactivity with similar peptides in healthy tissues [Linette et al., 2013, Blood]. Furthermore, the downregulation of HLA expression by tumor cells remains a significant challenge for long-term efficacy [Nature Reviews Drug Discovery, 2023].

Other names

pMHC complexPeptide-HLA-A*02 complexAntigen-HLA complexMHC-peptide complexHLA-A*02:01-peptide complex

Therapeutic agents target this complex by utilizing engineered T-cell receptors (TCRs) or TCR-bispecific molecules to recognize the specific peptide-HLA-A*02 interface, subsequently triggering T-cell mediated cytotoxicity against the antigen-presenting tumor cell [Nathan et al., 2021, NEJM; Merchant et al., 2024, Lancet].