Conclusion

The immune activity of NK cells is mediated by a large number of cell surface receptors that recognize different ligands and mediate different signalling pathways. Natural killer cells are one of the arms of the innate immune system, and are particularly interesting because they are able to differentiate between self and non-self cells, not by the absence of MHC I-presented molecules, but rather by their loss. This finely regulated activity comes from a balance between activating and inhibiting receptors that constantly sense the environment around the cell and generate a response that considers all the stimuli present.
NKp30 is a natural cytotoxicity trigger and its role on NK cell response to several stimuli is well explored, in particular in tumour settings. The usage of efficient NKp30 agonists would constitute a tremendous tool in immuno-oncology because it would simultaneously make use of both the specificity and the potency conferred by this receptor.
NKp30 is the target of several antibodies that have been used in immunotherapy regimens. Due to the inherent characteristics of the process, antibody production and usage is far from being a straightforward option when compared with the use of smaller and more affordable drugs. The development of specific and potent drugs, targeting the binding site of NKp30 and generating the same response, is of utmost importance.
The structure of NKp30 has been resolved both in its free and ligand-bound forms, and the ligand-binding region is well characterized. However, important aspects of NKp30-mediated NK cell activation arise not only from direct ligand binding but also from other affected residues. All structural data available in the literature, reviewed here, indicate that the design of specific and effective drugs requires not only binding to the adequate site, but also the ability to replicate ligand-induced conformational changes, in particular Arg67 displacement.
Targeting NKp30 with small molecules, such as peptides or low molecular weight ligands, should be considered as a new strategy to trigger immune responses against cancer prompted by NK cells. NKp30-targeted therapies have been proven efficient, as demonstrated by CAR-T cell expressing chimeric NKp30 receptors, that were found able to destroy B7-H6+ cells (Zhang, Wu & Sentman, 2012). This strategy, however, presents major drawbacks regarding the production and cost of CAR-T cells. The work of Phillips et al. (Phillips, Romeo, Bitsaktsis & Sabatino, 2016) provided important insights regarding the activation of NK cell response with small peptides, but more affordable and comprehensive strategies should be developed in the future as part of a new branch of cancer immunotherapy.