**3. Cancer immune evasion from NK cells**

where NK cell receptors can interact with their respective ligands. Given sufficient activation signals, NK cell cytoskeletal rearrangements are initiated, which result in the polarization of NK cell lytic granules toward the immunological synapse, where they eventually fuse and release their cytotoxic contents on to the target cell [50]. In contrast to CTLs, NK cells have their cytotoxic granules preformed before target cell recognition, and so their release is initially constrained until sufficient signalling is achieved. NK cells have also been shown to establish cytoskeletal polarity more slowly than CTLs, and to have a unique sensitivity to minor interference with cytoskeletal dynamics [51]. This stepwise progression in activa‐ tion events with specific requirements for synergistic signalling may provide a mechanistic explanation of how the spontaneous cytotoxic capacity of NK cells is regulated [52]. **Figure 2** outlines NK cell activation events at the immunological synapse with a tumour target cell.

20 Natural Killer Cells

**Figure 2.** Activating immunological synapse between NK cell and tumour target. NK cell encounter with a tumour cell target generates an immunological synapse at the point of contact. If the ligand combination on the tumour target engages NK cell activating receptors sufficiently, cytoskeletal rearrangements take place resulting in granule polarization

and the eventual release of cytotoxic granules on to the target cell. NK: natural killer cell.

Although the development of any malignancy is under surveillance by immune cells, tumour cells can still obtain means to escape from the immune system and proliferate. The recent addition of immune evasion as an emerging 'hallmark' of cancer, sheds lights on growing evidence in support of cancer evasion of immune cells [53]. Malignant cells acquire a set of biological capabilities during their development, allowing them to overcome recognition and elimination by the immune system. These capabilities are acquired with the assistance of inflammatory cells and soluble factors in the tumour microenvironment, which play an active role in the tumour development process. Kiessling et al. proposed that cancer evasion from NK cells involves an early stage of tumour formation and growth, which is associated with antigen‐specific tolerance, and a later stage, which induces a state of immunodeficiency [54]. Cancer immunoediting, as proposed by Dunn et al. argues that less immunogenic vari‐ ants are positively selected during tumour formation as they have a better chance of sur‐ vival in a normal immunological environment [55]. This led to the formulation of the three Es of cancer immunoediting; elimination, equilibrium and escape [56]. The elimination phase involves tumour eradication by immune cells. Any tumour cells that survive the elimination phase enter the equilibrium phase. During this phase, immune cells and tumour cells are in a dynamic equilibrium, with selective pressure exerted on tumour cells, such that only the less immunogenic variants survive. In the escape phase, tumour cell variants which are positively selected in the equilibrium phase continue to grow.

Tumours can evade NK cell attack directly by insufficient expression of ligands for NK cell activation receptors, such that the activation threshold for NK cell granule exocytosis is not met. Once successful evasion from NK cell attack is achieved, the tumour cells cre‐ ate the microenvironment necessary for continued growth. There are several strategies for direct evasion from NK cells by tumour targets. For example, tumours have been shown to reduce expression or shed ligands for important NK cell receptors. The NKG2D ligands UBLP2, MICA and MICB are commonly shed by tumour cells to evade NK cell attack through NKG2D recognition. Alternatively, tumour cells can increase MHC class I, soluble MIC and FasL expression in order to increase NK cell inhibitory signalling [30, 57, 58]. The secretion of soluble factors such as IL‐10, TGF‐β and indoleamine 2, 3‐dioxygense (IDO) by tumour targets suppresses the adaptive immune response to exhibit significantly less anti‐tumour capacity [59–63].

Tumour cells employ numerous cell types from the immune system for indirect NK cell eva‐ sion mechanisms. Tumour cells have been reported to recruit, myeloid‐derived suppressor cells (MDSCs), regulatory T cells, which release immunosuppressive Th2 cytokines and phagocytes, which release reactive oxygen species (ROS) to inhibit NK cell function [64]. Macrophages found in the tumour microenvironment can be classified as M1 or M2. The M1 subtype is associated with tumour control, through pro‐inflammatory cytokine and ROS secre‐ tion, whereas the M2 subtype promotes tumour growth and invasion through the production of anti‐inflammatory cytokines, upregulation of scavenging receptors and tissue remodelling [65]. Excess ROS in the tumour microenvironment can lead to tumour cell lysis. The Warburg effect, by which tumour cells rely mostly on glycolysis for energy production, enables cancer cells to resist ROS‐related death and gain survival advantage for metastasis [66].

Tumour cells can also impair dendritic cell (DC) function to prevent NK cell priming, by changing their expressions of IL‐6, IL‐10, vascular epithelial growth factor or GM‐CSF. Finally, tumour cells have also been shown to lower NK cell count by decreasing the numbers of lym‐ phoid progenitor cells [67]. **Figure 3** describes different tumour immune evasion strategies from NK cells.
