Tumor-expressed stress ligands and altered-self antigens (NKG2DL)

Tumor-expressed stress ligands and altered-self antigens represent a diverse group of molecules upregulated on cells experiencing physiological stress, such as oncogenic transformation, DNA damage, or viral infection [PMID: 21844392]. The most prominent members of this group include the MHC class I polypeptide-related sequence A and B (MICA/B) and the UL16-binding protein (ULBP) family, which are often referred to as stress ligands [UniProt: Q29983, Q29980]. Altered-self antigens also encompass neoantigens and post-translationally modified proteins that the immune system recognizes as foreign despite their host origin [PMID: 26642352]. These ligands serve as critical signals for the immune system, primarily by binding to activating receptors like NKG2D on Natural Killer (NK) cells and CD8+ T cells [PMID: 31105153]. In healthy tissues, these ligands are typically absent, but they are frequently overexpressed in many cancers, making them attractive targets for therapies like NKG2D-based CAR-T cells (e.g., CYAD-01) [Celyad Oncology, 2023]. However, tumors often evade these responses by shedding ligands into soluble forms, which act as decoys to neutralize immune cells [PMID: 12191486]. Consequently, therapeutic efforts focus on both direct targeting and preventing the loss of these surface markers to restore immune surveillance.

Other names

NKG2D ligandsStress-induced ligandsMHC class I-related sequence A/B (MICA/B)UL16-binding proteins (ULBPs)NeoantigensTumor-associated antigens (TAAs)RAET1 family

Activation of NKG2D-based chimeric antigen receptors (CARs), stabilization of surface ligands via monoclonal antibodies, and blockade of proteolytic ligand shedding.