T-Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis

Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Research (Impact Factor: 9.33). 05/2012; 72(9):2162-71. DOI: 10.1158/0008-5472.CAN-11-3687
Source: PubMed


T-regulatory cells (Tregs) are found infiltrating tumors in a vast array of tumor types, and tumor-infiltrating Tregs are often associated with a poor clinical outcome. Tregs are potent immunosuppressive cells of the immune system that promote progression of cancer through their ability to limit antitumor immunity and promote angiogenesis. Here, we discuss the ways in which Tregs suppress the antitumor immune response and elaborate on our recent discovery that Tregs make significant direct contributions to tumor angiogenesis. Further, we highlight several current therapies aimed at eliminating Tregs in cancer patients. Given the multifaceted role of Tregs in cancer, a greater understanding of their functions will ultimately strengthen future therapies.

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Available from: Andrea Facciabene, Oct 27, 2014
    • "All of these mechanisms suggest that the enlarged Treg population consists of a mixture of both nTreg (thymic and peripheral) as well as pTreg. Importantly, elevated Treg numbers and their highly suppressive function not only help tumors to evade from a productive immune surveillance (Facciabene et al., 2012), but also represent major hurdles towards successful immunotherapy (Curiel et al., 2004; Fehervari and Sakaguchi, 2005; Jacobs et al., 2012). Thus, Treg may provide an ideal target to increase cancer immune-surveillance and their initial description refuelled the hope of tumor-immunologists that cancer vaccination may be re-vitalized after years of frustrating research almost exclusively producing negative results. "
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    ABSTRACT: Immune escape is a hallmark of cancer. Regulatory T cells (Treg) have been described to maintain peripheral tolerance. The role of Treg in cancer is ambiguous, as they are central inhibitory regulators in solid tumors, whereas during inflammation-driven tumorigenesis they prevent cancer initiation by restraining inflammation. As a consequence, under conditions with chronic inflammation that may initiate malignant transformation, application rather than depletion of Treg may be helpful. In solid tumors, however, the success story of immune-activating antibodies targeting checkpoint molecules of T cell activation fuels the hope that Treg inactivation or depletion may additionally boost anti-tumor immune response. In this review we summarize important aspects on the dual role of Treg in cancer to provide a rationale for future Treg targeting attempts. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • "We found that administration of GA-A significantly suppressed metastasis of EL4 lymphoma cells to the liver, which correlated with improved survival. While Tregs are often associated with a poor clinical outcome [Facciabene et al., 2012], this study did not find any significant changes in Treg cells in vehicle versus GA-A treated mice. By contrast, we have found GA-A treatment attenuates EL4 tumor growth and metastasis by a marked inhibition of MDSC populations in the host, which could be regulated via the STAT3 pathway [Kujawski et al., 2008]. "
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    ABSTRACT: Lymphoma is a potentially life threatening disease. The goal of this study was to investigate the therapeutic potential of a natural triterpenoid, Ganoderic acid A (GA-A) in controlling lymphoma growth both in vitro and in vivo. Here, we show that GA-A treatment induces caspase-dependent apoptotic cell death characterized by a dose-dependent increase in active caspases 9 and 3, up-regulation of pro-apoptotic BIM and BAX proteins, and a subsequent loss of mitochondrial membrane potential with release of cytochrome c. In addition to GA-A's anti-growth activity, we show that lower doses of GA-A enhance HLA class II-mediated antigen presentation and CD4+ T cell recognition of lymphoma in vitro. The therapeutic relevance of GA-A treatment was also tested in vivo using the EL4 syngeneic mouse model of metastatic lymphoma. GA-A-treatment significantly prolonged survival of EL4 challenged mice and decreased tumor metastasis to the liver, an outcome accompanied by a marked down-regulation of STAT3 phosphorylation, reduction myeloid-derived suppressor cells (MDSCs), and enhancement of cytotoxic CD8+ T cells in the host. Thus, GA-A not only selectively induces apoptosis in lymphoma cells, but also enhances cell-mediated immune responses by attenuating MDSCs, and elevating Ag presentation and T cell recognition. The demonstrated therapeutic benefit indicates that GA-A is a candidate for future drug design for the treatment of lymphoma. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
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    • "These data demonstrate that macrophage cell function is critically involved in angio- and arteriogenesis (Figure 1). Given the role of T cell-derived cytokines on macrophage polarization and activation it is obvious that alteration in T cell activation will also affect angiogenesis and arteriogenesis, and will thus bring another level of complexity to the effect of immune cells on vascular biology (Starnes et al., 2001; Naldini et al., 2003; Stabile et al., 2003, 2006; Facciabene et al., 2012). "
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    ABSTRACT: Macrophages are not only involved in inflammatory and anti-infective processes, but also play an important role in maintaining tissue homeostasis. In this review, we summarize recent evidence investigating the role of macrophages in controlling angiogenesis, metabolism as well as salt and water balance. Particularly, we summarize the importance of macrophage tonicity enhancer binding protein (TonEBP, also termed nuclear factor of activated T-cells 5 [NFAT5]) expression in the regulation of salt and water homeostasis. Further understanding of homeostatic macrophage function may lead to new therapeutic approaches to treat ischemia, hypertension and metabolic disorders.
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