Strategies to enhance NK cell function for the treatment of tumors and infections

Abstract

Natural killer (NK) cells are innate immune cells equipped with the ability to rapidly kill stressed cells that are neoplastic or virally infected. These cells are especially important in settings where these stressed cells downregulate MHC class I molecules and evade recognition by cytotoxic T cells. However, the activity of NK cells alone is often suboptimal to fully control tumor growth or to clear viral infections. Thus, the enhancement of NK cell function is necessary to fully harness their antitumor or antiviral potential. In this review, we discuss how NK cell function can be augmented by the modulation of signal transduction pathways, by the manipulation of inhibitory/activating receptors on NK cells, and by cytokine-induced activation. We also discuss how some of these strategies are currently impacting NK cells in the treatment of cancer and infections.

FIG. 1:

The manipulation of NK cell signaling pathways and the removal of negative regulators of NK cell activation signaling pathways may enhance NK cell cytotoxicity and cytokine production. This figure depicts both the critical signaling pathways downstream of activating receptors that drive NK cell effector functions and those that inhibit it. Activating receptors converge on SLP-76, which drives the activation of PLCγ, Vav, and PI3K. Downstream signals emanating from these enzymes are critical for NK cell cytotoxicity and inflammatory cytokine production. Negative regulators of these pathways are depicted by yellow stars. The disruption of negative regulators of proximal signaling pathways or those directly associated with inhibitory receptor function (PTEN, SHIP, and SHP-1) results in hyporesponsive NK cells. In contrast, targeting negative regulators of distal signaling pathways that are not directly associated with inhibitory receptor function (DGKζ, Cbl) result in enhancement of NK cell function.

FIG. 2:

NK cell cytotoxicity and cytokine production can be enhanced by modulating KIR function on NK cells. This figure depicts the different ways KIRs can be manipulated to enhance NK cell anti-tumor cytotoxicity. A. NK cell inhibitory KIRs can be blocked by the anti-KIR monoclonal antibody IPH2101, allowing for enhanced signaling downstream of activating receptors and enhanced target cell lysis. In this example, KIR2DL-1/HLA-C2 interaction is blocked by the IPH2101 antibody. B. Allo-HSCT can be KIR/HLA-mismatched, whereby the recipient cells lack HLA ligand for the KIR expressed on donor cells. This mismatch prevents negative signaling downstream of the donor KIR, enhancing signaling downstream of activating receptors. In this example, the donor expresses KIR2DL-1 and its ligand HLA-C2 but the recipient lacks HLA-C2, leading to NK cell allo-reactivity. C. Donor NK cells can also be selected for activating KIRs, where binding to its HLA ligand on host tumor cells potentiates NK cell activity and allows for anti-tumor activity. In this example, the donor expresses KIR2DS1 but lacks its ligand HLA-C2. The recipient expresses HLA-C2 that is recognized by KIR2DS1 by donor NK cells, leading to NK cell allo-reactivity.

FIG. 3:

NK cell cytotoxicity and cytokine production can be enhanced by treatment with small molecules that redirects and activates NK cells or by engineering a chimeric antigen receptor on the NK cell surface. A. Bispecific antigen killer engagers (BiKEs) are small molecules that engage two sites, linking the activating receptor CD16 on the NK cell to a tumor antigen, resulting in ADCC. B. Trispecific killer-cell engagers (TriKEs) are a derivate of BiKEs that also include IL-15 to further enhance NK cell activation. TriKEs promote NK cell survival and proliferation, in addition to inducing ADCC. C. NK cells can be transduced to express a chimeric antigen receptor (CAR) directed towards a specific tumor antigen, which upon binding can initiate NK cell-mediated tumor cell lysis.