Macrophage Migration Inhibitory Factor Contributes to the Immune Escape of Ovarian Cancer by Down-Regulating NKG2D

Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
The Journal of Immunology (Impact Factor: 4.92). 07/2008; 180(11):7338-48. DOI: 10.4049/jimmunol.180.11.7338
Source: PubMed


The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells. Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers.

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Available from: Jörg Wischhusen, Oct 14, 2015
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    • "Alternatively, SD-208, a TGF-β receptor I kinase inhibitors, restores the lytic activity of polyclonal NK cells against glioma cells in the presence of recombinant TGF-β or of TGF-β-containing glioma cell supernatant (71). This molecule is able to restore NKG2D expression on NK cells, whose expression was altered in vitro by cancer cell lines supernatants or direct inhibition with recombinant TGF-β (72). "
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    ABSTRACT: Despite evidence of cancer immune-surveillance, which plays a key role in tumor rejection, cancer cells can escape immune recognition through different mechanisms. Thus, evasion to Natural killer (NK) cell-mediated anti-tumor activity is commonly described and is mediated by various mechanisms, mainly cancer cell-induced down-regulation of NK-activating receptors (NCRs, NKG2D, DNAM-1, and CD16) as well as up-regulation of inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs, NKG2A). Alterations of NK cells lead to an impaired recognition of tumor cells as well as a decreased ability to interact with immune cells. Alternatively, cancer cells downregulate expression of ligands for NK cell-activating receptors and up-regulate expression of the ligands for inhibitory receptors. A better knowledge of the extent and the mechanisms of these defects will allow developing pharmacological strategies to restore NK cell ability to recognize and lyse tumor cells. Combining conventional chemotherapy and immune modulation is a promising approach likely to improve clinical outcome in diverse neoplastic malignancies. Here, we overview experimental approaches as well as strategies already available in the clinics that restore NK cell functionality. Yet successful cancer therapies based on the manipulation of NK cell already have shown efficacy in the context of hematologic malignancies. Additionally, the ability of cytotoxic agents to increase susceptibility of tumors to NK cell lysis has been studied and may require improvement to maximize this effect. More recently, new strategies were developed to specifically restore NK cell phenotype or to stimulate NK cell functions. Overall, pharmacological immune modulation trends to be integrated in therapeutic strategies and should improve anti-tumor effects of conventional cancer therapy.
    Frontiers in Immunology 03/2014; 5:122. DOI:10.3389/fimmu.2014.00122
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    • "In this context, a recent study by our group in melanomas reported that NK cell function may be suppressed by IDO-generated l-kynurenine (a tryptophan-derived toxic metabolite) (71). Finally, also the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to inhibit the NKG2D expression in peripheral blood (PB) NK cells derived from ovarian cancer patients (72) (Figure 1A). "
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    ABSTRACT: Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection.
    Frontiers in Immunology 03/2014; 5:87. DOI:10.3389/fimmu.2014.00087
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    • "Similarly, the downregulation of MHC class I-related chain A (MICA) expression impedes the detection of tumor cells by innate cytotoxic effector cells through the engagement of the NKG2D-activating receptor [48,49]. Additionally, ovarian tumor cells overexpress molecules that counteract the cytotoxic activities of immune cells: CA125 binds the NK-cell inhibitory receptor (KIR) siglec-9, thereby protecting themselves from NK-mediated lysis [50,51]; the macrophage migration inhibitory factor (MIF) downregulates NKG2D-activating receptor expression on NK-cells [52]. Furthermore, engagement of programmed death-1 (PD-1) on CD8+ T-cells by programmed death-1 ligand-1 (PD-L1) expressed by ovarian tumor cells impairs the effector functions of these lymphocytes [24,53]. "
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    ABSTRACT: Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women, and there has been no substantial decrease in the death rates due to EOC in the last three decades. Thus, basic knowledge regarding ovarian tumor cell biology is urgently needed to allow the development of innovative treatments for EOC. Traditionally, EOC has not been considered an immunogenic tumor, but there is evidence of an immune response to EOC in patients. Clinical data demonstrate that an antitumor immune response and immune evasion mechanisms are correlated with a better and lower survival, respectively, providing evidence for the immunoediting hypothesis in EOC. This review focuses on the immune response and immune suppression in EOC. The immunological roles of chemotherapy and surgery in EOC are also described. Finally, we detail pilot data supporting the efficiency of immunotherapy in the treatment of EOC and the emerging concept that immunomodulation aimed at counteracting the immunosuppressive microenvironment must be associated with immunotherapy strategies.
    Journal of Translational Medicine 06/2013; 11(1):147. DOI:10.1186/1479-5876-11-147 · 3.93 Impact Factor
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