Dickkopf-related protein 1-specific T-cell receptor (DKK1-TCR)

Dickkopf-related protein 1 (DKK1)-specific T-cell receptors (TCRs) are specialized immune receptors that recognize specific peptide fragments derived from the DKK1 protein when presented by Major Histocompatibility Complex (MHC) molecules, most commonly HLA-A*02:01 [1][2]. DKK1 is a secreted glycoprotein and a potent inhibitor of the Wnt/beta-catenin signaling pathway, which is frequently hijacked by various cancers to promote growth and survival [3]. In multiple myeloma, DKK1 is highly overexpressed and contributes significantly to the development of osteolytic bone disease by inhibiting osteoblast differentiation [1][4]. Because DKK1 is highly expressed in tumor cells but has limited expression in most healthy adult tissues, it serves as an attractive target for T-cell-based immunotherapies [2]. TCR-engineered T-cell (TCR-T) therapy involves isolating or engineering these specific TCRs and expressing them in a patient's T lymphocytes to redirect their cytotoxic activity against DKK1-positive tumor cells [5]. Upon binding to the DKK1 peptide-MHC complex, the TCR triggers T-cell activation, leading to the targeted destruction of the cancer cell through the release of cytotoxic granules [1][5]. Clinical applications are primarily focused on hematological malignancies like multiple myeloma and various solid tumors, though challenges such as potential on-target off-tumor toxicity and the immunosuppressive tumor microenvironment remain areas of active research [2][4]. Citations: [1] Qian, J., et al. (2007). Blood. [2] Betts, B. C., et al. (2011). Clinical Cancer Research. [3] Niehrs, C. (2006). Oncogene. [4] Heath, D. J., et al. (2009). Blood. [5] D'Agostino, M., et al. (2020). Frontiers in Immunology.

Other names

DKK1-peptide-specific TCRDickkopf-1-specific T-cell receptorDKK1-specific TCRDKK1-targeted T-cell receptor

Recognition of DKK1-derived peptides presented by HLA-A*02:01 molecules on the surface of tumor cells, leading to T-cell activation and subsequent granzyme/perforin-mediated apoptosis of the target cell.