NKG2D ligands (MICA, MICB, ULBPs) (NKG2DL)

This target refers to a specific cellular phenotype characterized by the downregulation of Major Histocompatibility Complex (MHC) class I molecules and the upregulation of stress-induced ligands [Ljunggren and Kärre, 1990; Diefenbach and Raulet, 2001]. This profile is a hallmark of many malignant cells and makes them susceptible to recognition and lysis by Natural Killer (NK) cells and certain T cell subsets [Groh et al., 1998]. The loss of MHC class I prevents inhibitory signaling through Killer-cell Immunoglobulin-like Receptors (KIRs), a concept known as the 'missing-self' hypothesis [UniProt P26718]. Simultaneously, the expression of stress ligands like MICA, MICB, and ULBPs triggers activating receptors, primarily NKG2D, on cytotoxic lymphocytes [PubMed 11491511]. Therapeutic strategies targeting this phenotype include NKG2D-based CAR-NK and CAR-T cells, such as CYAD-01, which utilize the extracellular domain of the NKG2D receptor to recognize multiple ligands [Celyad Oncology]. Additionally, monoclonal antibodies like 7C6 are being developed to prevent the proteolytic shedding of MICA/B, which tumors use as a decoy to evade immune detection [Science, 2018]. Small molecules like HDAC inhibitors are also used to pharmacologically upregulate these ligands to enhance the efficacy of immunotherapy [PubMed 21149604]. Clinical challenges include the potential for off-tumor toxicity if ligands are expressed on healthy tissues under physiological stress. Overall, this target represents a broad-spectrum approach to treating diverse solid and hematological malignancies.

Other names

Tumor cells with low or absent MHC class I and expression of stress-induced ligandsStress-induced ligandsMICA/BUL16-binding proteinsMissing-self/Induced-self phenotypeNKG2D-Ls

Activation of the NKG2D receptor on Natural Killer (NK) cells and cytotoxic T cells to induce targeted lysis of cells that lack inhibitory MHC class I signals and express activating stress ligands.