Natural killer group 2 member D ligands (NKG2D ligands) (NKG2DL)

Tumor cell surface stress ligands, primarily comprising MHC class I polypeptide-related sequences A and B (MICA/B) and the UL16-binding protein (ULBP) family, are proteins that become upregulated in response to cellular stress, DNA damage, or malignant transformation (Waldhauer & Steinle, 2008, Oncogene). These ligands serve as critical 'eat-me' signals for the immune system, specifically acting as the primary targets for the NKG2D (Natural Killer Group 2 Member D) receptor found on Natural Killer (NK) cells and Cytokine-Induced Killer (CIK) cells. Immuncell-LC is an autologous CIK cell therapy that leverages this interaction to identify and eliminate residual cancer cells, particularly in patients with hepatocellular carcinoma (Lee et al., 2015, Gastroenterology). When the NKG2D receptor on the therapeutic CIK cells binds to these ligands, it initiates a signaling cascade that results in the directed secretion of cytotoxic granules, such as perforin and granzymes, leading to the apoptosis of the target tumor cell. However, many tumors develop resistance by proteolytically shedding these ligands from their surface, creating soluble decoys (e.g., sMICA) that impair the efficacy of the immune response by downregulating receptor expression (Groh et al., 2002, Nature).

Other names

MHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBP1-6)Retinoic acid early transcript 1 (RAET1)Stress-induced ligandsTumor-associated stress ligands

Immuncell-LC consists of autologous cytokine-induced killer (CIK) cells that express the NKG2D receptor; this receptor binds to stress-induced ligands (MICA/B, ULBPs) on the tumor cell surface, triggering the release of perforin and granzymes to induce tumor cell lysis (Lee et al., 2015, Gastroenterology).