Human epidermal growth factor receptor 2 peptide–Major Histocompatibility Complex (HER2 pMHC)

The Human epidermal growth factor receptor 2 (HER2) peptide–Major Histocompatibility Complex (MHC) is a molecular assembly found on the surface of cells, where intracellularly processed HER2 protein fragments (peptides) are presented by MHC molecules for immune surveillance (Slingluff, 2011). This complex is distinct from the full-length HER2 receptor protein, as it allows the immune system to see and target HER2-positive cells through T-cell receptor (TCR) recognition (Dao et al., 2013). In many cancers, such as breast and gastric cancer, HER2 is overexpressed, leading to an increased density of these pMHC complexes on the tumor cell surface (Mittendorf et al., 2014). Therapeutic strategies targeting this complex include peptide vaccines, such as Nelipepimut-S (E75), which prime the patient's own T-cells to recognize the specific HER2 peptide presented by HLA-A2 (Greene et al., 2014). Additionally, adoptive T-cell therapies (TCR-T) and TCR-like antibodies are being developed to directly bind the pMHC and induce tumor cell lysis (Schmitt et al., 2013). Because these therapies are HLA-restricted, patient selection based on specific HLA types, most commonly HLA-A*02:01, is essential for therapeutic efficacy (Saha et al., 2014). The complex plays a central role in cancer immunotherapy by expanding the targetable space of HER2 beyond the cell surface protein to include intracellularly derived epitopes. However, challenges such as HLA downregulation by tumors and potential cross-reactivity with healthy tissues remain significant hurdles in clinical development.

Other names

HER2/neu peptide-HLA complexpHER2/HLA-A2HER2-derived peptide-MHC complexERBB2 peptide-MHC complex

Induction of peptide-specific cytotoxic T-lymphocyte (CTL) responses and TCR-mediated recognition leading to tumor cell lysis (Slingluff, 2011; Dao et al., 2013).