Natural Cytotoxicity Triggering Receptors

Among the known activating receptors, NKG2D is by far the best characterized. It has been argued that, because NKG2D has a signalling pathway that does not overlap with the inhibitory signalling pathway of KIRs, its triggering is less susceptible to inhibitory ligands. At the same time, several studies have highlighted the importance of NCRs as part of the main mechanisms by which NK cells kill tumour targets (Pegram, Andrews, Smyth, Darcy & Kershaw, 2011). In fact, one study demonstrated that lymphoma cells are able to grow in vivo in the absence of NCR+ NK cells in mutant mice, but in wild-type mice, tumours were completely rejected over time (Halfteck, Elboim, Gur, Achdout, Ghadially & Mandelboim, 2009).
NCRs are expressed exclusively by NK cells and are extremely important in their activation. Of the four NCRs currently known, three are constitutively expressed (NKp30, NKp46 and NKp80) and one is expressed only in activated NK cells (NKp44) (Barrow, Martin & Colonna, 2019; Moretta et al., 2001). Engagement of these receptors by their ligands transduces a strong activation signal to the cell. Signal transduction by NCRs happens through ITAM motifs of associated proteins DAP12, in NKp44, FcεRIγ and CD3ζ in NKp30 and NKp46 (Kruse, Matta, Ugolini & Vivier, 2014; Moretta et al., 2001). NKp80 has been described only recently and its signalling is transduced through a hemITAM motif (Bartel, Bauer & Steinle, 2013). Interestingly, NKp44 presents three alternative mRNA splice variants, one of which bears in its intracellular portion an ITIM motif. The different levels of expression of these variants define the signalling arising from NKp44 engagement (Parodi et al., 2019).
The surface density of NCRs varies amongst individuals and is directly correlated with the ability to actively eliminate tumour cells. Moreover, lysis of certain NK-sensitive tumours can be averted by simultaneously blocking the activity of NKp30, 44 and 46, showcasing the relevance of these molecules (Biassoni et al., 2001; Moretta et al., 2001). Contrarily to what happens to NKG2D, NCRs NKp30 and NKp46 are not upregulated upon cytokine treatment. This demonstrates that the NCR density at the NK cell surface is remarkably stable and its underexpression (termed NCRdull) has been correlated with poor prognosis in cases of leukaemia (Fauriat et al., 2007) and non-small cell lung cancer (Charrier et al., 2019).
NCRs have been shown to recognise a multitude of ligands, including bacterial-, viral- and parasite-derived proteins, as well as stress-induced proteins (Kruse, Matta, Ugolini & Vivier, 2014). NKp30 interacts with a broad range of ligands without an obvious structural similarity, including viral, parasitic and tumoral proteins(Kruse, Matta, Ugolini & Vivier, 2014). NKp30, for instance, has been shown to interact with B7-H6 and BAT3, two proteins that share no homology (Pende et al., 1999). Binding of heparin and heparan sulphate sequences is also a puzzling observation. These sequences are widely expressed in all cells, but NCRs seem to be able to distinguish between the ones presented by tumoral and normal cells (Kruse, Matta, Ugolini & Vivier, 2014).
NKp30 has been regarded as a possible target for future immunotherapies due to its importance in mediating the anti-tumour effects of NK cells in both solid tumours and haematological malignancies (Correia, Fogli, Hudspeth, da Silva, Mavilio & Silva-Santos, 2011; Delahaye et al., 2011; Zhang, Wu & Sentman, 2012).