**4. NK cells in tumor immunosurveillance and cancer**

NK cells are innate cellular components that regulate adaptive immune responses in the immune surveillance of cancer. Primary immunodeficiencies affecting NK cells were associated with higher rates of malignancy and a higher risk of developing various types of cancer [54, 55]. NK cells have been shown to control the growth and metastasis of transplantable tumors in numerous mouse models by antibody depletion of NK cells [56].

NK cells can eliminate tumors that downregulate expression of MHC class I (**Figure 2b**), possibly in response to selective pressure exerted by CD8+ T cells. Furthermore, NK cells can kill tumor cells that retain full expression of MHC class I if they have upregulated ligands that engage activating NK cell receptors, thus overriding the inhibitory signals (**Figure 2c**).

For example, NKG2D ligand expression on tumor cells induces NK cell activation and is sufficient to overcome inhibitory signals delivered by MHC class I receptors, thereby enabling NK cells to eliminate tumors expressing normal levels of MHC class I [48, 57]. Mice deficient of NKG2D (*Klrk1−/−*) are more susceptible to tumorigenesis [58] confirming the crucial role of NKG2D in tumor immunosurveillance.

However, tumor cells are able to evade immunosurveillance by using multiple mechanisms. Tumor cells can secrete inhibitory cytokines such as transforming growth factor-β (TGFβ) that suppresses the activity of NK cells. Furthermore, tumor cells can express inhibitory receptor-specific ligands such as glucocorticoid-induced TNFR-related protein (GITR) that can downmodulate activating receptors NKG2D on NK cells. To escape to NK cell immunosurveillance, tumor cells can also secrete immunomodulatory molecules such as prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), adenosine, TGFβ, and interleukin-10 (IL-10). Tumor cells can proteolytically shed NKG2D ligands (NKG2DLs) leading to a decreased amount of NKG2DL and to the production of soluble ligands that downmodulate NKG2D receptor on NK cells [59, 60]. Finally, secretion of immunosuppressive molecules or expression of NKG2DLs by cells of the tumor microenvironment can downmodulate NKG2D receptor on NK cells.

and kill target cells coated with antibodies [50]. DNAM-1 ligands CD112 and CD155 have been described in different pathological conditions, and recent evidence indicates that their

All of these activating receptors promote cytotoxicity and cytokine production responses

Inhibitory receptors are able to prevent the activation of NK cells and have been thought of as fail-safe mechanisms to prevent attack on normal cells and tissues. In general, these receptors express one or more immunoreceptor tyrosine-based inhibition motifs (ITIM), and they recruit SH2-containing phosphatase-1 (SHP1), SH2-containing phosphatase-2 (SHP2), and/ or SH2-containing inositol phosphatase (SHIP) proteins upon binding to their ligands [51]. These phosphatases prevent the activation of cellular signaling cascades by inhibiting phos-

The inhibitory receptors encompass two distinct classes: the monomeric type I glycoprotein of the immunoglobulin superfamilies KIR2DL and KIR3DL [51], leukocyte immunoglobulinlike receptors (ILT2), and the hetero-dimeric C-type lectin-like receptor (CTLR) called CD94/

NK cells are innate cellular components that regulate adaptive immune responses in the immune surveillance of cancer. Primary immunodeficiencies affecting NK cells were associated with higher rates of malignancy and a higher risk of developing various types of cancer [54, 55]. NK cells have been shown to control the growth and metastasis of transplantable

NK cells can eliminate tumors that downregulate expression of MHC class I (**Figure 2b**), pos-

tumor cells that retain full expression of MHC class I if they have upregulated ligands that

For example, NKG2D ligand expression on tumor cells induces NK cell activation and is sufficient to overcome inhibitory signals delivered by MHC class I receptors, thereby enabling NK cells to eliminate tumors expressing normal levels of MHC class I [48, 57]. Mice deficient of NKG2D (*Klrk1−/−*) are more susceptible to tumorigenesis [58] confirming the crucial role of

However, tumor cells are able to evade immunosurveillance by using multiple mechanisms. Tumor cells can secrete inhibitory cytokines such as transforming growth factor-β (TGFβ) that suppresses the activity of NK cells. Furthermore, tumor cells can express inhibitory receptor-specific ligands such as glucocorticoid-induced TNFR-related protein (GITR) that

engage activating NK cell receptors, thus overriding the inhibitory signals (**Figure 2c**).

T cells. Furthermore, NK cells can kill

through stimulating intracellular protein tyrosine kinase cascades.

NKG2A (natural killer group protein 2 family member A) [52, 53].

**4. NK cells in tumor immunosurveillance and cancer**

sibly in response to selective pressure exerted by CD8+

NKG2D in tumor immunosurveillance.

tumors in numerous mouse models by antibody depletion of NK cells [56].

expression is regulated by cellular stress.

**3.2. Inhibitory NK cell receptors**

56 Natural Killer Cells

phorylation of proteins.

Soluble NKG2DLs have been detected at high levels in the serum of cancer patients [61] and might be used as a diagnostic marker [62]. Tumor cells can escape immunosurveillance by the secretion of soluble factors such as lactate dehydrogenase, leading to NKG2DLs expression on healthy host myeloid cells [63]. NKG2D Downregulation could be the result of its chronic exposure to NKG2D ligand on tumor cells [64]. Recent work in a mouse model suggests that a shed NKG2D ligand, MULT1, stabilizes expression of NKG2D on NK cells and increase their antitumor activity [65]. Controlling NKG2DL expression level on tumors provides an attractive therapeutic strategy for immunotherapy.

In patients and animal models, impaired NK cells or NK cell deficiency have been associated not only with recurring viral infections, but also with an increased incidence of various types of cancer [55]. Tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. In fact, during tumor development and progression, many malignant cells acquire the ability either to evade from NK cell recognition or to impair NK cell function.

Cells undergoing malignant transformation often downregulate their expression of MHC class I molecules, and the absence of inhibitory signaling on NK cells permits their function. A defective immunity has been well established in different types of cancer. The imbalance of immune status is inclined to immunosuppression in cancer patients, which results in tumor immune evasion. Such immunosuppression is characterized by a decrease in NK cell numbers in peripheral blood and a decreased tumor infiltrate as compared to normal tissues. Moreover, in many types of cancer, a defective expression of activating receptors and overexpression of inhibitory receptors is observed [66].

The role of NK cells against parasites that may promote or impede carcinogens is poorly understood. Chronic inflammation is a key feature in carcinogenesis associated with helminth infections. For example, *Strongyloides stercoralis* infection was associated with an increased occurrence of lymphoid cancers [67]. An association of colorectal cancer with chronic *S. stercoralis* infection has also been reported in a Columbian patient [68]. This nematode is not only a cofactor for the development of lymphoid cancers induced by HTLV-1 [69] but is also associated with the development of colon adenocarcinoma by activating the host immune response. A study reports a case of Strongyloides infection in a 72-year-old man presenting a large population of cells (NK-LGL) with a natural killer phenotype abnormally activated and diagnosed with NK-LGL leukemia [70]. The role of NK cells in the immune response to Strongyloides is not defined, but it is possible that an abnormal or clonal expansion of NK cells could suppress antihelminth immunity. Activated NK cells, perhaps producing interferon, suppressed the T-helper 2 response that previously controlled the Strongyloides infection.
