Tumor-associated ligands for Natural Killer cell activating receptors (NKR-L)

Tumor-associated ligands for Natural Killer (NK) cell activating receptors are a diverse group of cell surface proteins that are upregulated on cells undergoing stress, malignant transformation, or viral infection [Zingoni et al., 2018, Frontiers in Immunology]. These ligands, which include the MHC class I polypeptide-related sequence A and B (MICA/B) and UL16-binding proteins (ULBPs), serve as critical "eat-me" signals by binding to activating receptors like NKG2D on NK cells and certain T cell subsets [Schmiedel & Mandelboim, 2018, Frontiers in Immunology]. Other notable ligands include B7-H6, which triggers NKp30, and CD155 (PVR) and CD112 (Nectin-2), which activate the DNAM-1 receptor [Brandt et al., 2009, Journal of Experimental Medicine]. In healthy tissues, these ligands are typically absent or sequestered, but oncogenic signaling and DNA damage pathways induce their expression to facilitate immune surveillance [Raulet et al., 2013, Nature Reviews Immunology]. However, tumors frequently evade this detection by proteolytically shedding these ligands from the cell surface, creating soluble decoys that inhibit NK cell function [Groh et al., 2002, Nature]. Therapeutic approaches targeting these ligands include monoclonal antibodies designed to stabilize surface expression by preventing shedding, bispecific engagers that bridge ligands to NK cells, and CAR-NK or CAR-T cells engineered with receptors like NKG2D to recognize and eliminate ligand-positive tumor cells [Ferrari de Andrade et al., 2018, Science].

Other names

Stress-induced ligandsNKG2D ligandsNK cell activating ligandsMICA/B and ULBPsB7-H6Nectin-like proteins

Activation of NK cell-mediated cytotoxicity through engagement of activating receptors (e.g., NKG2D, NKp30, DNAM-1) or prevention of ligand shedding to maintain surface density.