Stress-induced ligands (NKG2D and DNAM-1 ligands) (SILs)

Stress-induced ligands (SILs) are a diverse group of cell surface proteins, including MICA/B, ULBPs, CD155, and CD112, that are upregulated on cells undergoing malignant transformation, viral infection, or DNA damage (Dhar & Wu, 2018). These ligands serve as critical recognition signals for the immune system by binding to activating receptors such as NKG2D and DNAM-1 (CD226) expressed on Natural Killer (NK) cells and certain T cell subsets (Shimasaki et al., 2020). In the context of CYNK-001, an allogeneic, placental-derived NK cell therapy, these ligands are the primary targets that facilitate the recognition and lysis of tumor cells (Celularity, 2024). CYNK-001 is enriched for NK cells that express high levels of these activating receptors to effectively engage with the stress ligands present on various hematologic and solid tumors (Sanchez-Correa et al., 2019). Upon binding, the NK cells undergo degranulation, releasing cytotoxic molecules like perforin and granzymes to induce apoptosis in the target cell. However, tumors often employ immune evasion strategies, such as the proteolytic shedding of MICA/B, which creates soluble decoys that can impair NK cell function (Zingoni et al., 2018). Understanding the density and variety of these ligands on target cells is essential for predicting the efficacy of CYNK-001 and similar NK-based immunotherapies.

Other names

NKG2D ligandsDNAM-1 ligandsMICAMICBULBP1-6CD155CD112PVRNectin-2Stress ligand–binding NK activating receptors on CYNK-001 – target cell ligands

Activation of NK cell-mediated cytotoxicity through the engagement of activating receptors (NKG2D, DNAM-1) with their respective stress-induced ligands on target cells.