The Influence of Physicochemical Microenvironment on NK Cells

If we were to engineer a potent tumor-killer cell, we would design it to have an induced cytotoxicity at the peculiar tumor microenvironment conditions. Surprisingly however, NK cells demonstrate the opposite behavior and in contrast to the desired augmentation of cytotoxicity at tumor site, they are repressed by hypoxia, acidification and low glucose levels which are considered as a hallmark of tumor microenvironment [20]. The local conditions in tumor are long recognized to be significantly hypoxic at less than half the pO2 of normal tissue, and down to anoxic [102]. Acidic pH is commonly referred to the tumor microenvironment, and lymphocytes cytotoxicity and proliferation abilities are suppressed by acidic environment [103]. Different measurements revealed that while lower pH is frequent, higher pH is also sometimes observed, and tumors might better be described to have less-stable pH ranging on wider spectrum than normal tissue, rather than only "acidic" [102].

Reactive oxygen metabolites in tumor microenvironment also suppress NK cytotoxicity, IL-2 responsiveness, and augment apoptosis [104]. Specific downreg-ulation of the zeta chain was observed in infiltrating NK cells of colorectal carcinoma [105]. NK cytotoxicity against the K562 target cells and against liver cancer cells was significantly reduced upon prolonged incubation at 1% oxygen, compared to 21% oxygen of ambient air and low oxygen also diminished the induction of cytotoxicity by IFNg [106]. It was recently demonstrated that human decidual NK cells promotes angiogenesis trough the secretion of PLGF and VEGF [107]. The pro-angiogenesis contribution of NK cells at early stages might aim to reduce the local danger of further transformation, while at later stages such activity might accidentally help to sustain tumor growth. In human clinical studies, the presence of infiltrating NK cells was reported to have a positive prognosis [16, 17], showing that the net effect of NK cells is antitumor, in spite of the suggested pro-tumor functions of other immune cells [108].

Tumors do not relay only on these environmental-conditions only and also secrete various factors that affect the function of local immune cells. For example, corticosteroids reduce the expression of NCRs [109]. Specific enzymatic oddities also impair NK activities, for example the expression of NKp46 and NKG2D was downregulated by the IDO product L-kynurenine [110]. The IL-10 and TGFb were more extensively studied and are therefore specifically discussed below.

Taken together, it seems as if NK cells are not well designed to exhibit their abilities at the harsh conditions of progressed tumors. This fact suggest that the antitumor effect of NK cells should be studied at early stages of tumor formation and that the antitumor effects of NK cells should better be examined at the tumor conditions.

9.11 IL-10

NK cells, under certain conditions, produce IL-10 [111]. IL-10, and TGFb, enhances the expression of the nonclassical class-I MHC molecule HLA-G [112] which in turn leads to the inhibition of NK activity [113]. IL-10 itself also inhibit the production IFNg, TNFa by NK cells [114].Cancerous cells may secrete IL-10 and gain autocrine stimulation to enhance their proliferation [115]. On the other hand, IL-10 can also stimulate NK activity [116]. The in vivo administration of IL-10 increased the plasma levels of granzymes, indicating increased NK and CTL activity [117]. Enhancement of NK cytotoxicity against tumor cell-line in vitro was demonstrated to result from post-translational downregulation of class-I MHC presentation by IL-10 [118]. Preclinical studies demonstrated that IL-10 has antitumor effect in vivo, which is suggested to be due to NK cells mainly [119-121].

9.12 TGF-p

Transforming Growth Factor b (TGFb) was demonstrated by many studies to play a major role in antitumor immunity [122]. NK cells lose IFNg secretion, cytotoxicity and proliferation capabilities once exposed to TGFb [123-125]. These effects were demonstrated in vivo by a gain-of-function experiments in which overexpression of TGFb rendered a highly immunologic tumor to become resistant to immune rejection [126]. In addition, specific interruption of TGFb signaling in NK and DCs was recently reported to affect NK homeostasis, and also had a major impact in regulation of NK activities such as IFNg production [127].

The mechanisms by which TGFb affects NK cell function are being revealed lately. TGFb was shown to generally antagonize the activity of the pro-inflammatory cytokines through SMAD2, 3 and 4, inhibiting both IFNg and T-bet expression in NK cells [128]. The expression of T-bet in NK cells is essential for their maturation, for proper expression of perforin, granzymeB and Runx1, and for the induction of enhanced IFNg production [129]. In addition, TGFb inhibit the expression of at least two major NK lysis receptors: NKp30 and NKG2D [130]. Beside the direct inhibitory effects of TGFb on NK activity, this cytokine also influence NK cells indirectly in the tumor microenvironment, for example, by inducing FoxP3 expression in regulatory T cells that thereafter suppress NK cell activity locally [122]. Thus, TGFb is a general inhibitor of NK functions and developing different strategies to overcome TGFb inhibition are desired.

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