Multiple myeloma cell surface ligands for Natural Killer cell activating receptors (MM-NKARL)

Multiple myeloma (MM) cells express a diverse array of ligands that trigger Natural Killer (NK) cell activation through receptors such as NKG2D, DNAM-1, NKp30, NKp44, and NKp46 [1]. Key ligands include MICA, MICB, and ULBP1-6 for NKG2D, and CD155 (PVR) and CD112 (Nectin-2) for DNAM-1 [2, 3]. These interactions are vital for the immune surveillance of malignant plasma cells, as NK cells utilize these signals to distinguish tumor cells from healthy tissue [4]. In MM, the expression of these ligands is often dysregulated; for instance, B7-H6 serves as a ligand for NKp30 and is frequently expressed on the surface of MM cells [5]. Therapeutic approaches, including the use of immunomodulatory drugs (e.g., Lenalidomide) and proteasome inhibitors (e.g., Bortezomib), have been shown to upregulate these ligands, thereby sensitizing MM cells to NK cell-mediated lysis [6]. However, MM cells can evade this response by shedding ligands like MICA into a soluble form, which acts as a decoy and impairs NK cell function [7]. Current research focuses on CAR-NK cells and bispecific engagers that target these ligands to overcome immune evasion in relapsed or refractory disease [8]. (Sources: [1] Bottino et al., 2005, Chem Immunol Allergy; [2] El-Sherbiny et al., 2007, Blood; [3] Pende et al., 2005, Blood; [4] Carbone et al., 2005, Blood; [5] Brandt et al., 2009, J Exp Med; [6] Fionda et al., 2015, Front Immunol; [7] Kaiser et al., 2007, Blood; [8] Wu et al., 2020, Front Immunol).

Other names

NKG2D ligandsDNAM-1 ligandsNatural cytotoxicity receptor ligandsNCR ligandsMICA/B and ULBPsCD155 and CD112B7-H6

Activation of Natural Killer (NK) cells through the binding of activating receptors (NKG2D, DNAM-1, NKp30, NKp44, NKp46) to their respective ligands on multiple myeloma cells, triggering the release of perforin and granzymes to induce tumor cell apoptosis.