Article

DC-HIL/Glycoprotein Nmb Promotes Growth of Melanoma in Mice by Inhibiting the Activation of Tumor-Reactive T Cells

Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section Medical Service, Dallas Veterans Affairs Medical Center, Dallas, Texas 75390-9069, USA.
Cancer Research (Impact Factor: 9.33). 07/2010; 70(14):5778-87. DOI: 10.1158/0008-5472.CAN-09-2538
Source: PubMed

ABSTRACT

DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8(+) T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL-knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy.

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    • "The notion that GPNMB is linked to melanomas with low-metastatic potential38 has been dispelled by subsequent studies that report high GPNMB expression in malignant cutaneous melanoma.32,91 In a murine melanoma model, it has been suggested that GPNMB promotes tumor growth via an immunosuppressive mechanism involving a block in T-cell activation.92 Interestingly, this study also reported that GPNMB could be released from melanoma cells in the form of exosomes, and that this dissemination of GPNMB might facilitate systemic immunosuppression of anti-tumor responses.92 "
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    • "Moreover, over-expression of GPMNB increases tumor cell invasion in vitro and promotes their metastasis in vivo (Onaga et al., 2003; Rich et al., 2003), potentially by up-regulating the expression of MMP-9 and MMP-3 (Ogawa et al., 2005), which promotes tumor metastasis(Rose and Siegel, 2010). Targeting GPMNB significantly inhibits GPMNB-positive melanoma cell growth in vivo (Tomihari et al., 2010). Even though this molecule has been proposed to be important in melanomas, there is no report of its expression in melanoma lesions in vivo. "
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    ABSTRACT: The presence of tumor-associated macrophages (TAMs) in melanomas is correlated with a poor clinical prognosis. However, there is limited information on the characteristics and biological activities of human TAMs in melanomas. In this study, we developed an in vitro method to differentiate human monocytes to macrophages using modified melanoma-conditioned medium (MCM). We demonstrate that factors from MCM-induced macrophages (MCMI-Mφ) express both M1-Mφ and M2-Mφ markers and inhibit melanoma-specific T-cell proliferation. Furthermore, microarray analyses reveal that the majority of genes up-regulated in MCMI-Mφ are associated with tumor invasion. The most strikingly up-regulated genes are CCL2 and MMP-9. Consistent with this, blockade of both CCL-2 and MMPs diminish MCMI-Mφ-induced melanoma invasion. Finally, we demonstrated that both MCMI-Mφ and in vivo TAMs express the pro-invasive, melanoma-associated gene, glycoprotein non-metastatic melanoma protein B. Our study provides a framework for understanding the mechanisms of cross-talk between TAMs and melanoma cells within the tumor microenvironment.
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    • "Gpnmb overexpression by virus-mediated gene transfer in a human glioma cell line resulted in a more invasive and metastatic phenotype, accompanied by enhanced expression of matrix metalloproteinase (MMP)-3 and MMP-9 (Rich et al. 2003). Tomihari et al. (2010) demonstrated using a mouse model that Gpnmb inhibits the activation of melanoma-reactive T lymphocytes and thereby promotes invasion. Moreover, an anti-Gpnmb monoclonal antibody that is conjugated with a cytotoxic agent has been subjected to clinical trials in patients with malignant glioma, breast cancer, and cutaneous melanoma (Tse et al. 2006; Pollack et al. 2007; Qian et al. 2008; Naumovski and Junutula 2010; Rose and Siegel 2010; Williams et al. 2010; Kuan et al. 2011). "
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Questions & Answers about this publication

  • Daniel Wehrung added an answer in Mice:
    Name of the tumor marker for malignant melanoma specific for Serum and Tissues?

    Hi 

    I want to know the names of markers for the Malignant melanoma specific for the Serum and Tissues.

    I'm using the mice model so these markers should be very specific for the mice. (Balb/c)

    Daniel Wehrung

    DC-HIL/GPNMB. 

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      [Show abstract] [Hide abstract]
      ABSTRACT: DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8(+) T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL-knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy.
      Full-text · Article · Jul 2010 · Cancer Research