Tumor cell surface stress ligands and missing-self determinants

Tumor cell surface stress ligands and missing-self determinants represent a conceptual group of molecules that regulate the immune system's ability to identify and eliminate malignant cells. Stress ligands, such as MICA, MICB, and ULBP proteins, are typically absent on healthy cells but become upregulated during oncogenic transformation, viral infection, or DNA damage, serving as 'eat-me' signals for Natural Killer (NK) cells and T cells via the NKG2D receptor (PMID: 11486057, 30305468). Conversely, 'missing-self' determinants refer to the loss or downregulation of Major Histocompatibility Complex (MHC) Class I molecules, a common tumor evasion tactic that inadvertently triggers NK cell activation by removing inhibitory signals normally transmitted through Killer-cell Immunoglobulin-like Receptors (KIRs) (PMID: 2212708). In the context of drug development, this target group is exploited through various immunotherapeutic strategies. Monoclonal antibodies like Monalizumab block the inhibitory NKG2A receptor from binding to HLA-E (a missing-self related ligand), thereby restoring NK cell activity (PMID: 30503213). Additionally, chimeric antigen receptor (CAR) therapies, such as CYAD-01, are engineered to use the NKG2D binding domain to target the broad array of stress ligands expressed on diverse tumor types. While promising for their ability to target multiple cancers with a single agent, challenges include the shedding of soluble ligands by tumors to decoy the immune system and the potential for off-target effects on healthy tissues undergoing physiological stress.

Other names

NKG2D ligandsStress-induced ligandsMissing-self signalsNK cell recognition ligandsMHC class I-related molecules

Enhancing anti-tumor immunity by either blocking inhibitory 'missing-self' signals (e.g., via KIR or NKG2A receptors) or by directly targeting and activating immune cells through stress-induced ligands (e.g., MICA/B binding to NKG2D).