Modulation of Tumor Recognition by NK Cells

NKG2D is involved in the prevention of tumor spread and tumor formation in mice [43]. Its human ligands, ULBPs, MICA and MICB proteins are expressed by several tumors. Numerous studies reported on the frequent expression of MICA and MICB, both on primary lesions and on metastases of melanomas, leukemic cells, gliomas and various carcinomas [61]. The ULBPs were also expressed by the same tumors, albeit at a low frequencies [61]. NKG2D-ligands are specifically induced by genotoxic stress, which contributes significantly also for tumor formation [62]. Recently, the BCR/ABL human oncogene was shown to induce MICA expression in leukemia cells [63]. With this regard it is important to mention that chronic contact with NKG2D-ligand expressing target cells might be unsafe to the NK cells as it can reduce the expression of NKG2D and other receptors and consequently reduce cytotoxicity [64].

Certain tumors develop mechanisms to overcome NKG2D-mediated killing by the downregulation of NKG2D ligands [61]. A naturally defective allele of MICA (MICA*010) was found in tumor cells and is not expressed to the cell surface [65]. In addition, many tumors produce soluble MICA and MICB proteins and such proteins were detected in the sera of cancer patients [61]. These soluble NKG2D ligands could either block NKG2D activity or modulate its expression [61, 15]. The mechanisms of soluble NKG2D ligands formation are only poorly understood [61]. Inhibition of metalloproteinase activity resulted in the MICA accumulation on tumor cells by preventing soluble MICA formation [66]. Soluble MICs could serve as a good diagnostic tool for disease progression in prostate carcinomas [67]. More recently, soluble MICA levels were reported to be significantly elevated in a big cohort of cancer patients and healthy individuals [68]. Soluble MICB protein was also found in many patients, but at surprisingly low-correlation with the soluble MICA [69]. This suggested that there are different mechanisms employed for the modulation of the MICA and MICB [69]. Other soluble NKG2D ligands such as ULBP2 were found in the supernatant of cultured tumor cells [70]. One mechanism of soluble ULBPs formation was discovered in gastric cancer cell lines, in which soluble ULBPs were generated by phosphatidylinositol-specific phospholipase C release of the GPI anchor [71]. As for MICA and -B, the soluble ULBPs were demonstrated to reduce the expression of the NKG2D receptor and consequently the cytotoxicity of NK cells [71].

The frequent modulation of NKG2D ligands in tumors probably reflects their significance in the antitumor activity. The chronic binding of the NKG2D ligands to their receptor and the cognate downregulation of NKG2D, resembles the anergy condition of T-cell after sub-optimal stimulation [72, 73]. Understanding the precise molecular mechanism of NK repression might enable the development of new treatment aimed at increasing NK activity and killing of tumor cells.

Other activating receptors are also involved in tumor recognition [41]. AML patients demonstrate poor NK cytotoxicity, due to a severe reduced expression of NKp30, NKp46 and NKp44 [74]. The mechanisms accounting for the NCRs down-regulation are unknown, but they are TGFb independent. Our in vitro experiments indicate that the expression of NKp30, NKp44 and NKp46 receptors is more stable on the surface of NK cells upon engagement, compared to NKG2D (Gross-Gonen T and Mandelboim O, manuscript in preparation). Thus, the NCRs might provide more rigid interactions with tumors. The critical role of the NCRs in tumor formation is demonstrated in mice lacking the NCR1 receptor. Upon 3MCA challenge the NCR1 knockout homozygous mice developed many more tumors [Gazit R and Mandelboim O, manuscript in preparation]. Thus, the NCRs play a key role in preventing tumor formation.

Other proteins which can impair NK activity are also secreted in the tumor microenvironment. For example, soluble HLA-A, B and C as well as the non-classical HLA-G molecule are secreted from tumor cells [75]. These soluble class-I MHC molecules aggregates to engage receptors on NK and T cells, resulting in the induction of apoptosis [75]. The ICAM-1 protein was also reported to appear as a soluble form in melanoma patients [76]. Soluble ICAM-1 can interact with the LFA-1 integrin (CD11a/CD18 heterodimer) [77], preventing NK adhesion to the tumor cells. With this regard, our study of LFA-1 on NK cells revealed an essential role for this receptor in killing of tumor cells-lines and primary melanoma cells [Sa'ar M and Mandelboim O, manuscript in preparation].

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