Tumor cells expressing stress-induced ligands for NK-92 activating receptors with reduced inhibitory HLA expression

This target refers to a specific malignant cell phenotype that is highly susceptible to the cytotoxic activity of NK-92 cells, a human natural killer cell line used in adoptive immunotherapy. These tumor cells are characterized by the upregulation of "stress-induced ligands," such as MHC class I polypeptide-related sequence A (MICA), MICB, and various UL16-binding proteins (ULBPs), which serve as "eat-me" signals for activating receptors like NKG2D on the NK-92 surface (Klingemann et al., 2016). Concurrently, these cells exhibit reduced or absent expression of Human Leukocyte Antigen (HLA) class I molecules, a common immune evasion tactic that inadvertently removes the "don't-eat-me" signals typically recognized by inhibitory Killer-cell Immunoglobulin-like Receptors (KIRs) (Garrido et al., 2016). Because NK-92 cells naturally lack most inhibitory KIRs, they are uniquely poised to attack cells that have lost HLA expression while expressing stress ligands (Suck et al., 2016). The interaction between the NK-92 activating receptors and the tumor's stress ligands triggers the formation of an immunological synapse and the polarized secretion of perforins and granzymes, resulting in rapid apoptosis and lysis of the target cell (Zhang et al., 2017). This cellular profile is a primary focus for developing "off-the-shelf" NK-cell therapies and chimeric antigen receptor (CAR)-modified NK-92 cells for treating both hematologic and solid tumors (Marcus et al., 2014).

Other names

NK-92 sensitive tumor cellsMHC-I deficient/stress-ligand positive tumor cellsNK-92 target cellsNKG2D-ligand expressing tumor cells

NK-92 cells exert direct cytotoxicity against target cells through the release of perforin and granzymes, triggered by the engagement of activating receptors (e.g., NKG2D) with stress-induced ligands (e.g., MICA/B) and the absence of inhibitory signals from HLA molecules (Suck et al., 2016; Klingemann et al., 2016).