Human epidermal growth factor receptor 2 peptide-major histocompatibility complex-specific T cell receptor (HER2-pMHC-specific TCR)

The HER2 peptide-MHC complex-specific T cell receptor (TCR) is a specialized heterodimeric protein complex expressed on the surface of CD8+ cytotoxic T cells. This receptor is engineered or naturally selected to recognize specific peptide fragments of the Human Epidermal Growth Factor Receptor 2 (HER2/neu) protein, such as the E75 (KIFGSLAFL) epitope, when they are presented by Major Histocompatibility Complex (MHC) Class I molecules, most commonly HLA-A*02:01 [1][2]. Unlike traditional HER2-targeted antibodies that bind to the extracellular domain of the protein, this TCR allows T cells to detect intracellularly processed HER2 antigens, expanding the range of targetable HER2-positive cells [3]. In the context of cancer immunotherapy, TCR-engineered T cell (TCR-T) therapies utilize these receptors to redirect a patient's immune system against HER2-overexpressing tumors, including breast, gastric, and lung carcinomas [4]. Upon binding to the HER2-pMHC complex, the TCR triggers a signaling cascade through the CD3 complex, resulting in the secretion of pro-inflammatory cytokines and the release of cytotoxic granules to induce tumor cell apoptosis [5]. However, a critical challenge in targeting this receptor is the potential for on-target off-tumor toxicity, as low levels of HER2 expression in vital organs like the heart and lungs can lead to severe adverse events [6].

Other names

HER2-specific TCRERBB2-specific T-cell receptorHLA-A*02:01/HER2(369-377) TCRHER2-pMHC TCRE75-specific T-cell receptor

The TCR specifically binds to HER2-derived peptides presented by MHC Class I molecules on the surface of tumor cells, initiating CD3-mediated signaling that leads to T-cell activation, cytokine release, and granzyme/perforin-mediated apoptosis of the target cell.