Stress-induced ligands of activating Natural Killer cell receptors (NKG2DL)

Stress-induced ligands are a diverse group of cell-surface proteins that are typically absent or expressed at low levels on healthy cells but become highly upregulated in response to cellular stress, such as DNA damage, oxidative stress, or malignant transformation (Source: PMID: 30305468). The most well-characterized members are the NKG2D ligands, which in humans include MHC class I polypeptide-related sequence A (MICA), MICB, and the six members of the UL16-binding protein (ULBP) family (Source: UniProt Q29983, Q29980). Other important ligands include B7-H6, which binds the NKp30 receptor, and CD155/CD112, which bind the DNAM-1 receptor (Source: PMID: 21441454, PMID: 28101063). These ligands serve as activating signals that trigger Natural Killer (NK) cells and cytotoxic T cells to eliminate the compromised cell (Source: PMID: 21807380). In oncology, many tumors develop mechanisms to evade this immune surveillance, such as the proteolytic shedding of ligands from the cell surface. This shedding results in soluble decoys that desensitize NK cells and reduce the density of activating signals on the tumor itself (Source: PMID: 31515463). Therapeutic interventions targeting these ligands include CAR-T cells engineered with the NKG2D receptor, bispecific killer cell engagers (BiKEs), and monoclonal antibodies designed to block the shedding process or facilitate antibody-dependent cellular cytotoxicity (ADCC). Clinical trials are currently exploring these modalities to treat both hematological malignancies and solid tumors where these ligands are overexpressed.

Other names

NKG2D ligandsMHC class I polypeptide-related sequence A/BMICAMICBUL16-binding proteinsULBPsB7-H6DNAM-1 ligandsPVRCD155Nectin-2CD112RAET1 proteins

Activation of NK cells and T cells via receptor-ligand binding; prevention of ligand shedding to maintain immune visibility.