NKG2D and DNAM-1 ligands

NKG2D and DNAM-1 ligands are a diverse group of cell-surface proteins expressed on acute myeloid leukemia (AML) cells that serve as critical recognition signals for Natural Killer (NK) cells and cytotoxic T cells. The NKG2D ligands, including MHC class I polypeptide-related sequence A/B (MICA/B) and UL16-binding proteins (ULBP1-6), along with DNAM-1 ligands such as CD155 (PVR) and CD112 (Nectin-2), are typically upregulated during malignant transformation or cellular stress (Pende et al., 2005, Blood). Interaction between these ligands and their respective activating receptors, NKG2D (KLRK1) and DNAM-1 (CD226), triggers the release of perforin and granzymes, leading to the lysis of leukemic blasts (Bottino et al., 2003, J Exp Med). In AML, these ligands are often downregulated or proteolytically shed to evade immune detection, making their stabilization a key therapeutic goal. Pharmacological agents like hypomethylating agents (Azacitidine) and HDAC inhibitors (Valproic acid) are used to induce ligand expression and sensitize cells to immunotherapy (Rohner et al., 2014, Frontiers in Immunology). Furthermore, novel cellular therapies such as NKG2D-based CAR-T cells (e.g., CYAD-01) are being developed to directly exploit this recognition axis for treating refractory AML.

Other names

NKG2D ligandsDNAM-1 ligandsNKG2DLDNAM-1LMICA/BULBPsCD155CD112Poliovirus receptorNectin-2

Enhancement of tumor cell susceptibility to NK cell-mediated lysis through the upregulation of surface ligands or direct targeting via chimeric antigen receptor (CAR) engineered immune cells.