**4. NK cell receptors as therapeutic targets in cancer immunotherapy**

As NK cell antitumor activity is regulated by numerous activating and inhibitory NK cell receptors, alterations in NK cell receptor expression and signaling underlie diminished cytotoxic NK cell function. Based on this and on predictive *in vitro* findings [6, 46–48, 67–70], cytokines, including IFNα, IL-2, IL-12, IL-15, and IL-18 have been used systemically or for *ex vivo*–activation and expansion of NK cells and have led to improved NK cells antitumor activity by increasing the expression of NK cell activating receptors and by inducing cytotoxic effector molecules [71–75]. Moreover, this cytokine-based therapy enhances NK cell proliferation and regulatory function, and it has been shown that it induces NK cells exhibiting cytokine induced memory-like properties [76] that represent a newly-defined NK cell subset with improved NK cell activity and longevity.

Considering the effect of tumor-derived immunosuppressive molecules on the decrease in the expression of activating NK cell receptors, early stage clinical trials have been introduced that use monoclonal antibodies, alone or in combination, to neutralize TGF-β, IDO, or PD-1 checkpoint inhibitor in different malignancies that led to improved antitumor NK cell function [77].

Since inhibitory KIR play prominent roles in regulating NK cell activation, therapeutic strategies in cancer to diminish KIR function have been developed. In autologous settings, antiinhibitory KIR monoclonal antibody therapy has been introduced to support autologous NK cell administration by rendering them with higher antitumor activity, as reported in AML and MM. On the other hand, allogeneic hematopoietic stem cell transplants (HSCT) based on partially KIR/HLA mismatched alloreactive NK cell transfer that relieve donor NK cells from inhibition by recipient's MHC class I molecules, show beneficial graft-versus-tumor (GvT) effect in both pediatric and adult high-risk leukemia [78].

Moreover, it has been recognized that classical and novel pharmacological agents, such as proteasome inhibitors or histonedeacetylase inhibitors and certain chemotherapeutics [72, 74, 75], upregulate cognate ligands for activating receptors on tumor cells and provide better NK cell antitumor response.

Also, a new effective approach, in clinical trials, designed to enhance NK cell—tumor cell interaction includes genetically modified NK cells expressing cytokine transgenes, chimeric antigen receptors (CARs), or overexpressing activating receptors that recognize NK cell ligands on tumor cells are showing promising results.

As it has been shown that therapeutic antibodies that are already in use for cancer treatment also trigger NK cell-mediated ADCC activity [79, 80] have been modified to increase binding of their Fc fragment to CD16 on NK cells. These therapeutic antibodies by binding CD16 receptor induce a potent activating signal, which overcomes inhibitory signals and results in both cytotoxicity and cytokine responses [81] that enhance NK cell activation against tumor cells.
