Interleukin 10 decreases MICA expression on melanoma cell surface

Abstract

Natural-killer group 2, member D (NKG2D) binds to a variety of ligands, including the major histocompatibility complex (MHC) class I chain-related proteins (MIC) and UL16-binding proteins (ULBP). It is regarded as a co-activating receptor on NK cells, having an important role in the cell-mediated immune response to tumours. We studied the influence of interleukin (IL)-10 on the regulation of MIC and ULBP expression on melanoma cells, and its effect on the cytotoxic function of NK cells in vitro.Here, we show that, in the presence of IL-10, FMS mel and BL mel cell lines decreased MICA and ULBP2 surface expression, whereas MHC class I did not change substantially on the cell surface. MICA mRNA levels decreased in IL-10-treated FMS and IL-10-transduced BL cell lines. Interestingly, we observed that MICB surface expression and its mRNA levels increased upon IL-10 treatment in a melanoma cell line. These changes in NKG2D ligands surface expression patterns owing to IL-10 treatment resulted in an effect on lysis susceptibility mediated by lymphocyte-activated killer cells, as tumour cell lines that displayed a higher decrease of MICA on their surface had lower levels of lysis. In addition, expression of CD107a was downregulated on the surface of NK cells following stimulation with IL-10-treated FMS cells. Our results suggest a novel function for IL-10 in the modulation of NKG2D ligand expression and in the control of cytotoxicity mediated by NKG2D/NKG2D ligand axis. Keywords: immune evasion; interleukin 10; melanoma cells; natural killer cell; NKG2D ligands Natural-killer group 2, member D (NKG2D) is a co-activating receptor expressed on NK cells. 1 It has also been identified on gd T, ab CD8 + T cells and in NKT cells in human beings. 2 NKG2D binds to a variety of ligands that resemble the major histocompatibility complex (MHC) class I proteins. [3][4][5] In human beings, the UL16-binding proteins (ULBP), 6,7 also denominated retinoic acid early transcript 1, 8 and MHC class I chain-related proteins A and B (MICA and MICB, respectively) 3,4 have been described. Ligands for NKG2D (NKG2DL) are rarely detectable on the surface of healthy cells, but they can be upregulated by cellular malignant transformation, viral infection and cellular stress, among other stimuli, such as chemotherapeutic drugs. [8][9][10][11] NKG2D and its ligands have a critical role in tumour immune surveillance. 5,12 In fact, NKG2D-deficient mice are defective in establishing a response against spontaneous malignancies. 13 In addition, there is evidence of an early induction of NKG2DL surface expression during spontaneous tumour genesis. 14 However, during the immunoediting process, tumour cells can interfere with NKG2D-mediated activity by different mechanisms, such as expression of tumourderived NKG2DL by exosomes and release of soluble forms of NKG2DL by metalloproteases or alternative splicing. 2,15-18 These molecules interact directly with NK cells and CD8 + T cells in an NKG2D-dependent manner, and strongly reduce the NKG2D-mediated cytotoxi...

Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells

“…For instance, the commensal bacteria may establish a regulatory milieu in the intestine, with increased expression of immuno-inhibitory cytokines such as TGF-β and IL-10. In this regard, it is notable that both TGF-β and IL-10 have been shown to downregulate NKG2D ligand surface expression [41,42]. In agreement with this, IL-10 KO mice were shown to have an increase in IEC NKG2D ligand expression.…”

“…In agreement with this, IL-10 KO mice were shown to have an increase in IEC NKG2D ligand expression. Similarly, IL-10 has previously been reported to restrict the expression of the human NKG2D ligand MICA in melanoma cells [42]. IL-10 KO mice naturally develop inflammation in the colon from 10 to 12 weeks of age [43]; however, in the present study, the NKG2D ligand expression on small IECs was investigated in the IL-10 KO mice before any development of clinical sign of colitis.…”

Temporary elimination of IL-10 enhanced the effectiveness of cyclophosphamide and BMDC-based therapy by decrease of the suppressor activity of MDSCs and activation of antitumour immune response

“…Elimination of IL-10 from tumour microenvironment presumably not only enabled the proper functioning of the cellular vaccines, but also induced activation of NK cells. It was reported that in the presence of IL-10 NK cells revealed decreased cytotoxic activity which is associated with changes in expression of NKG2D ligands on the surface of tumour cells (Serrano et al, 2011;Urosevic and Dummer, 2003). In our case, activation of NK-dependent antitumour response may be also associated with reduced MDSC suppressor activity observed after the application of anti-IL-10 Abs.…”

Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy

“…In addition to biological effects on immune cells as highlighted above (refer to section ''IL-10 production by immune cells and its role in immune and inflammatory responses'') and counteracting DC activity [27,86,87], IL-10 downregulates human leukocyte antigen and intercellular adhesion molecule expression on melanoma cell lines [75] and inhibits the function of transporter associated with antigen processing-1/2 (TAP1/2) in tumor cells [88]. IL-10 inhibits NKG2D ligand expression on melanoma cells and suppresses cytotoxicity mediated by NKG2D/NKG2D-ligand interaction [89]. Furthermore, IL-10 induces HLA-G molecules that prevent attack by NK cells [90].…”