Therapeutic potential and challenges of natural killer cells in treatment of solid tumors

Abstract

Natural killer (NK) cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing, requiring one-to-one target engagement and site-directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells, and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME) and augment adaptive immune responses by promoting differentiation, activation, and/or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes, and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.

Keywords: KIR-HLA interactions; NK-cell subsets; cancer stem cells; clinical application; tumor microenvironment.

Figure 1

Immune suppressive mechanisms of the solid tumor microenvironment. Tumor-derived immunosuppressive mechanisms include secreted cytokines and chemokines that recruit and sustain immature and suppressive immune cells. These in turn secrete Th2 factors that propagate the cycle to create a chronic anti-inflammatory environment that promotes and predominates malignant progression (left). NK cell therapy has the potential to reverse the anti-inflammation to engender dominant pro-inflammatory signaling through secretion of IFN-γ, Th1 cytokines, and activation of both innate and adaptive immune cells (right). By elimination of tumor cells and immature suppressive cells (e.g., iDCs, MDSCs, cancer stem cells), NK cells have the potential to reverse the anti-inflammatory signals and eliminate tumor progression. iDCs, immature dendritic cells; mDCs, mature dendritic cells; MDSCs, myeloid derived suppressor cells; PGE2, prostaglandin E-2; IDO, indoleamine-2,3-dioxygenase; VEGF, vascular endothelial growth factor; TGFβ, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; IFN-γ, interferon-gamma; IL, interleukin; iNOS, inducible nitric oxide synthase; ROS, reactive oxygen species; CTLs, cytotoxic T lymphocytes (CTLs); Tregs, regulatory T lymphocytes; CSC, cancer stem cells.

Figure 2

NK cell activation and target recognition. (A) Tolerance to self. NK cells express inhibitory and activating receptors on the surface and when interaction with cognate ligands for both activating and inhibitory receptors is balanced, NK cells remain tolerant and unable to kill the target cell e.g., normal unstressed self-cells that express class I HLA ligands for inhibitory receptors. (B) Missing self. A malignantly transformed cell may downregulate class I HLA but concomitantly express stress induced ligands that are recognized by NK cell activating receptors. A dominant activating signal is transduced that outweighs the inhibitory signals, resulting in NK cell activation and subsequent lysis of the target cell. (C) Altered self. Some cancer types express normal levels of class I HLA but concomitantly over-express stress-induced ligands e.g., GBM. Only when the activation signal transduced by ligation of stress ligands to cognate activating receptors overcomes the inhibitory signal, will NK cells become activated to lyse the target cell.

Figure 3

Immunological synapse and NK cell mediated cell death. Upon synapsing with target cells, NK cells release proteolytic enzymes, granzyme A and B, as well as perforins that induce necrotic death. The ligation of Fas Ligand (FasL) to Fas/CD95 receptor together with the binding of TNF-α to death receptors induce apoptosis of the tumor cell. NK cell FcγRIII (CD16) recognizes antibody Fc constant domains resulting in cytokine secretion and NK cell mediated antibody dependent cellular cytotoxicity (ADCC). The most abundantly secreted cytokines are TNF-α and IFN-γ.