Natural killer cell receptor ligands (NKRL)

Natural killer (NK) cell receptor ligands are a diverse group of cell surface proteins expressed by tumor or stressed cells that interact with activating and inhibitory receptors on NK cells to regulate immune surveillance (Vivier et al., 2011, PMID: 21212348). Activating ligands, such as MHC class I polypeptide-related sequence A (MICA), MICB, and UL16-binding proteins (ULBPs), are typically upregulated in response to cellular stress, DNA damage, or malignant transformation, signaling the NK cell to eliminate the target via the NKG2D receptor (Zingoni et al., 2018, PMID: 30405618). Conversely, inhibitory ligands, including non-classical MHC class I molecules like HLA-E and HLA-G, provide self signals that interact with receptors like NKG2A or KIRs to prevent NK cell-mediated lysis of healthy tissues (Shimasaki et al., 2020, PMID: 32433590). In the context of cancer, tumors often downregulate activating ligands or overexpress inhibitory ones to evade immune detection, a process often facilitated by the proteolytic shedding of ligands like MICA into a soluble form (sMICA) that acts as a decoy (Duan et al., 2019, PMID: 31139145). Therapeutic strategies targeting these ligands or their corresponding receptors aim to restore or enhance NK cell activity, utilizing monoclonal antibodies like monalizumab (targeting NKG2A) or lirilumab (targeting KIRs), as well as bispecific NK cell engagers (BiKEs) and CAR-NK cell therapies (Demaria et al., 2019, PMID: 31160737).

Other names

Tumor/stressed cell ligands for NK activating/inhibitory receptorsStress-induced ligandsNKG2D ligandsKIR ligandsNK cell checkpoint ligandsInduced-self ligands

Enhancement of NK cell-mediated cytotoxicity by blocking inhibitory ligand-receptor interactions or promoting activating ligand-receptor engagement (Shimasaki et al., 2020, PMID: 32433590).