NKG2D ligands and MHC Class I molecules (NKG2DL / MHC-I)

Stress-induced ligands (such as MICA, MICB, and ULBP1-6) and the absence of MHC Class I molecules (the "missing-self" signal) represent a critical recognition axis for Natural Killer (NK) cells, including the engineered iPSC-derived NK cell therapy FT538. Tumor cells frequently upregulate stress-induced ligands due to DNA damage or oncogenic transformation, which are then recognized by activating receptors like NKG2D on NK cells to trigger cytolysis (PubMed: 29461445). Conversely, many tumors downregulate MHC Class I molecules to evade T-cell detection; this loss of "self" markers removes the inhibitory signals typically transmitted through Killer-cell Immunoglobulin-like Receptors (KIRs), thereby sensitizing the tumor to NK cell attack (PubMed: 11244036). FT538 is specifically engineered to exploit these pathways by incorporating a high-affinity, non-cleavable CD16 receptor to enhance antibody-dependent cellular cytotoxicity (ADCC) and an IL-15 receptor fusion for enhanced persistence and activity without exogenous cytokines (Fate Therapeutics, 2024). Additionally, FT538 features a CD38 knockout to prevent fratricide when used in combination with CD38-targeting monoclonal antibodies like daratumumab, allowing for a synergistic attack on tumor cells that express both stress ligands and specific tumor antigens (ClinicalTrials.gov: NCT04614636).

Other names

Stress-induced ligandsMissing-self ligandsMICA/BULBP1-6HLA Class IMajor Histocompatibility Complex Class INKG2D-L

Activation of NK cells through the binding of stress-induced ligands (MICA/B, ULBPs) to the NKG2D receptor and the relief of inhibition (missing-self) caused by the downregulation of MHC Class I molecules, which normally bind to inhibitory KIR receptors (Fate Therapeutics, 2024).