Human epidermal growth factor receptor 2-derived peptides presented on major histocompatibility complex (HER2-pMHC)

Human epidermal growth factor receptor 2 (HER2)-derived peptides presented on the major histocompatibility complex (MHC) are critical targets for T-cell-based cancer immunotherapies (Schnittger et al., 2014, PMID: 25103457). Unlike monoclonal antibodies that target the surface-expressed HER2 protein, these targets consist of short peptide fragments, such as E75 or GP2, that are processed intracellularly and displayed by HLA molecules (Patel et al., 2020, PMID: 33166134). This presentation mechanism allows the immune system to recognize and eliminate cells that overexpress the HER2 proto-oncogene through the activation of cytotoxic T-lymphocytes (CTLs) (Mittendorf et al., 2012, PMID: 22585461). Therapeutic interventions targeting these complexes include peptide vaccines, TCR-engineered T-cells (TCR-T), and TCR-mimetic antibodies (Immatics, 2023). These therapies are highly specific but are limited by HLA restriction, meaning they are only effective in patients with specific MHC alleles, such as HLA-A*02:01 (Schnittger et al., 2014, PMID: 25103457). Clinical applications primarily focus on preventing recurrence in HER2-positive breast cancer and treating other HER2-expressing malignancies like gastric and ovarian cancers (Patel et al., 2020, PMID: 33166134). A significant challenge in targeting HER2-pMHC is the potential for tumor immune escape through the downregulation of MHC molecules or the loss of antigen processing machinery (Mittendorf et al., 2012, PMID: 22585461). Additionally, safety concerns include on-target off-tumor toxicity if the targeted peptides are presented at low levels on healthy tissues (Immatics, 2023).

Other names

HER2/HLA complexHER2 peptide-MHCErbB2-derived peptides on MHCpMHC (HER2)HER2-derived HLA-restricted antigens

Recognition of the peptide-MHC complex by T-cell receptors (TCRs) to induce a targeted cytotoxic immune response against HER2-expressing cells (Patel et al., 2020, PMID: 33166134).