CD8+ T-cell receptors specific for glycoprotein 100 (280–288)–HLA-A*0201 complexes (gp100(280-288)-HLA-A*0201 TCR)

CD8+ T-cell receptors (TCRs) specific for the peptide 946–HLA-A*0201 complex are specialized immune receptors that recognize a specific epitope from the glycoprotein 100 (gp100) antigen. Peptide 946, also known as gp100(280-288) or by its sequence YLEPGPVTA, is a highly immunogenic nonamer presented by the HLA-A*02:01 MHC Class I molecule on the surface of melanoma cells. These TCRs are found on cytotoxic T lymphocytes and play a critical role in the surveillance and destruction of malignant melanocytes. Upon binding to the peptide-MHC complex, the TCR initiates a signaling cascade that leads to T-cell activation, cytokine production (such as IFN-gamma), and the release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in the target cell. This interaction is a major focus of cancer immunotherapy, including the development of peptide vaccines like the Peptide 946 Melanoma Vaccine and engineered TCR therapies. A notable clinical application is tebentafusp (Kimmtrak), a bispecific molecule that utilizes a high-affinity TCR domain specific for this complex to redirect T cells against uveal and cutaneous melanoma. Therapeutic use of these TCRs or their targets can lead to autoimmune side effects, such as vitiligo and uveitis, due to the expression of gp100 in normal pigment-producing cells.

Other names

Peptide 946-specific TCRYLEPGPVTA-specific TCRgp100-specific T-cell receptorgp100(280-288)-specific TCRCD8+ T-cell receptors specific for peptide 946–HLA-A*0201 complexes

Vaccines containing the gp100(280–288) peptide (Peptide 946) stimulate the expansion and activation of endogenous CD8+ T cells expressing these specific TCRs. Bispecific molecules like tebentafusp incorporate a high-affinity TCR domain to bind the gp100-HLA complex and an anti-CD3 domain to redirect T cells toward tumor cells, bypassing the need for endogenous TCR recognition.