T-cell receptor-HER2 peptide-HLA complex (TCR-HER2-HLA)

The T-cell receptor (TCR) recognition of HER2-derived peptides presented by Human Leukocyte Antigen (HLA) molecules is a specialized target for advanced cancer immunotherapies. This target consists of a tripartite complex where a specific HER2 peptide fragment (such as E75 or GP2) is nested within the groove of an HLA molecule (typically HLA-A*02:01) and recognized by a cognate TCR (Schumacher & Schreiber, 2015). Unlike traditional HER2-targeted antibodies that bind the extracellular domain, TCR-based approaches can recognize peptides derived from both surface and intracellular HER2 protein turnover, potentially expanding the range of targetable epitopes (Yossef et al., 2018). Therapeutic modalities targeting this complex include TCR-engineered T-cells (TCR-T) and TCR-mimetic bispecifics, which redirect the immune system to eliminate HER2-positive tumor cells with high precision (Liu et al., 2022). However, the clinical application of this target is constrained by the requirement for patient HLA matching and the risk of severe on-target, off-tumor toxicities. Historical clinical trials have demonstrated that even low-level HER2 expression in normal tissues, such as the lungs and heart, can lead to life-threatening adverse events when targeted by highly potent T-cell therapies (Morgan et al., 2010). Consequently, current development efforts emphasize the selection of TCRs with optimal affinity and the implementation of safety switches to manage potential toxicities in patients with HER2-overexpressing malignancies.

Other names

HER2-pMHC complexHER2 peptide-MHC interactionHLA-A*02:01/HER2(369-377) complexTCR-HER2-HLA interactionHER2 peptide-HLA-A2 complex

T-cell mediated cytotoxicity triggered by the specific binding of engineered T-cell receptors or TCR-mimetics to HER2-derived peptides presented by HLA molecules.