NKG2D ligands and CD1d (NKG2DL/CD1d)

The target group 'Tumor cell surface ligands and stress-induced markers recognized by autologous Natural Killer and Natural Killer T cells' refers to a set of proteins upregulated on the surface of cells undergoing malignant transformation or physiological stress. The most prominent members are the NKG2D ligands, which include MHC class I polypeptide-related sequences A and B (MICA and MICB) and the UL16-binding proteins (ULBPs) (PMID: 21844392). These ligands are recognized by the activating receptor NKG2D, expressed on Natural Killer (NK) cells and certain T cell subsets, triggering a potent cytotoxic response. Additionally, this category includes CD1d, a non-polymorphic MHC-like molecule that presents lipid antigens to Natural Killer T (NKT) cells, bridging the innate and adaptive immune systems (PMID: 17291281). In the context of oncology, these markers serve as critical danger signals that allow the immune system to identify and destroy tumor cells. However, tumors often employ evasion strategies such as downregulating these ligands or using proteolytic enzymes to shed them from the cell surface; these soluble forms (e.g., sMICA) can act as decoys to inhibit immune cell function (PMID: 15905584). Therapeutic strategies targeting these markers include CAR-T and CAR-NK cells (e.g., CYAD-01) that utilize the NKG2D receptor to recognize tumor cells, as well as monoclonal antibodies designed to prevent ligand shedding or enhance their visibility to the immune system (PMID: 29427423). Safety considerations include the potential for off-target effects on healthy tissues that may express these markers under non-malignant stress conditions.

Other names

Tumor cell surface ligands and stress-induced markers recognized by autologous Natural Killer and Natural Killer T cellsMHC class I polypeptide-related sequence A (MICA)MHC class I polypeptide-related sequence B (MICB)UL16-binding proteins (ULBPs)Stress-induced ligandsNKG2D ligandsCD1d

Activation of cytotoxic lymphocytes (NK cells, CD8+ T cells, and NKT cells) through the engagement of activating receptors (NKG2D) or TCR-mediated recognition of lipid antigens (CD1d), leading to the release of perforin and granzymes and subsequent tumor cell lysis.