Induced and natural regulatory T cells in human cancer

University of Pittsburgh Cancer Institute, Pathology, Hillman Cancer Center , 5117 Centre Ave, Pittsburgh, 15213, USA .
Expert opinion on biological therapy (Impact Factor: 3.65). 07/2012; 12(10):1383-97. DOI: 10.1517/14712598.2012.707184
Source: PubMed

ABSTRACT Introduction: Evidence suggests that FOXP3(+)CD25(high)CD4(+) regulatory T cells (Treg) which accumulate in cancer may have beneficial or unfavorable effects on prognosis. The presence in tumor-associated inflammatory infiltrates of two subsets of Treg with distinct phenotypic and functional profiles might explain these conflicting observations. Areas covered: Human inducible (i) Treg arising by tumor-driven conversion of conventional CD4(+) T cells are highly suppressive, therapy-resistant Treg which down-regulate anti-tumor immune responses, promoting tumor growth. Natural (n) Treg, normally responsible for maintaining peripheral tolerance, control cancer-associated inflammation, which favors tumor progression. This division of labor between nTreg and iTreg is not absolute, and overlap may be common. Nevertheless, iTreg play a critical and major role in cancer and cancer therapy. The tumor microenvironment determines the type, frequency and suppression levels of accumulating Treg. Expert opinion: In cancer, a selective removal or silencing of iTreg and not of nTreg should be a therapeutic goal. However, the implementation of this challenging strategy requires further studies of cellular and molecular crosstalk among immune cells in the tumor microenvironment.

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    • "+ T-cell subsets after subimmunogenic stimulation, e.g. in the presence of immunosuppressive cytokines as IL-10 or TGF-β and therefore were termed inducible Tregs (iTregs) (Mills, 2004). These iTregs are considered to be mainly responsible for a controlled decline of an immune response against pathogens (Povoleri et al., 2013) and suppress anti-tumour immune responses, thereby promoting tumour growth (Whiteside et al., 2012). Due to these different roles in the immune system much effort has been put into the phenotypical discrimination of iTregs and nTregs. "
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    ABSTRACT: Within the population of regulatory T cells (Tregs) natural Tregs (nTregs) and inducible Tregs (iTregs) can be distinguished. Although information about Tregs in swine exists, porcine iTregs were not under investigation yet. In this study, Foxp3(+) iTregs were generated from CD4(+)Foxp3(-) T cells by in vitro stimulation in the presence of IL-2 and TGF-β. In comparison to ex vivo Tregs these iTregs had a similar suppressive capacity on the proliferation of CD3-stimulated PBMC, caused higher levels of IL-10 in PBMC/Treg co-cultures, but did not suppress IFN-γ levels. The Ikaros family member Helios is currently discussed to distinguish iTregs and nTregs or to serve as an activation marker of Tregs. In this study, we demonstrate the cross-reactivity of an anti-mouse/human Helios mAb with porcine Helios. Flow cytometric analyses with this antibody showed that porcine iTregs do not express Helios after in vitro iTreg induction. Nevertheless, thymic Foxp3(+) T cells, which arise at the CD4/CD8α single-positive stage of T-cell development and are defined as nTregs, entirely expressed Helios. Although this might suggest the suitability of Helios as an nTreg - iTreg differentiation marker we also found that Helios(-) Tregs displayed a phenotype of naïve CD4(+) T cells in vivo. Since iTregs are by definition activated/ differentiated Tregs, this finding precludes that all Helios(-) Tregs are iTregs and thus also the use of Helios as a selection marker for porcine nTregs. Furthermore, Helios(+) Tregs displayed a more differentiated phenotype indicating that Helios might rather serve as a Treg activation/ differentiation marker. Copyright © 2014. Published by Elsevier Ltd.
    Developmental & Comparative Immunology 12/2014; 49(2). DOI:10.1016/j.dci.2014.12.005 · 3.71 Impact Factor
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    • "Acta (2014), forkhead box protein 3 (FoxP3) expression in the highly suppressive, therapy-resistant inducible T regulatory cells (iTreg) [162], which promote tumor progression by down-regulating effector T cells [163]. Evaluating the consequences of Orai1 and TRPC1 inhibition on the immune response against cancer development is, therefore, mandatory before introducing this approach into a pre-clinical setting. "
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    ABSTRACT: Endothelial progenitor cells (EPCs) may be recruited from bone marrow to sustain the metastatic switch in a number of solid cancers, including breast cancer (BC) and renal cellular carcinoma (RCC). Preventing EPC mobilization causes tumor shrinkage. Novel anti-angiogenic treatments have been introduced in therapy to inhibit VEGFR-2 signaling; unfortunately, these drugs blocked tumor angiogenesis in pre-clinical murine models, but resulted far less effective in human patients. Understanding the molecular mechanisms driving EPC proliferation and tubulogenesis in cancer patients could outline novel targets for alternative anti-angiogenic treatments. Store-operated Ca(2+) entry (SOCE) regulates the growth of human EPCs, and it is mediated by the interaction between the endoplasmic reticulum Ca(2+)-sensor, Stim1, and the plasmalemmal Ca(2+) channels, Orai1 and TRPC1. EPCs do not belong to the neoplastic clone: thus, unlike tumor endothelium and neoplastic cells, they should not remodel their Ca(2+) toolkit in response to tumor microenvironment. However, our recent work demonstrated that EPCs isolated from naïve RCC patients (RCC-EPCs) undergo a dramatic remodeling of their Ca(2+) toolkit by displaying a remarkable drop in the endoplasmic reticulum Ca(2+) content, by down-regulating the expression of inositol-1,4,5-receptors (InsP3Rs), and by up-regulating Stim1, Orai1 and TRPC1. Moreover, EPCs are dramatically less sensitive to VEGF stimulation both in terms of Ca(2+) signaling and of gene expression when isolated from tumor patients. Conversely, the pharmacological abolition of SOCE suppresses proliferation in these cells. These results question the suitability of VEGFR-2 as a therapeutically relevant target for anti-angiogenic treatments and hint at Orai1 and TRPC1 as more promising alternatives. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 10/2014; DOI:10.1016/j.bbamcr.2014.10.024 · 5.30 Impact Factor
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    ABSTRACT: CD4+Foxp3+ T regulatory (Treg) cells control many facets of immune responses ranging from autoimmune diseases, to inflammatory conditions, and cancer in an attempt to maintain immune homeostasis. Natural Treg (nTreg) cells develop in the thymus and constitute a critical arm of active mechanisms of peripheral tolerance particularly to self antigens. A growing body of knowledge now supports the existence of induced Treg (iTreg) cells which may derive from a population of conventional CD4+ T cells. The fork-head transcription factor (Foxp3) typically is expressed by natural CD4+ Treg cells, and thus serves as a marker to definitively identify these cells. On the contrary, there is less consensus on what constitutes iTreg cells as their precise definition has been somewhat elusive. This is in part due to their distinct phenotypes which are shaped by exposure to certain inflammatory or "assault" signals stemming from the underlying immune disorder. The "policing" activity of Treg cells tends to be uni-directional in several pathological conditions. On one end of the spectrum, Treg cell suppressive activity is beneficial by curtailing T cell response against self-antigens and allergens thus preventing autoimmune diseases and allergies. On the other end however, their inhibitory roles in limiting immune response against pseudo-self antigens as in tumors often culminates into negative outcomes. In this review, we focus on this latter aspect of Treg cell immunobiology by highlighting the involvement of nTreg cells in various animal models and human tumors. We further discuss iTreg cells, relationship with their natural counterpart, and potential co-operation between the two in modulating immune response against tumors. Lastly, we discuss studies focusing on these cells as targets for improving anti-tumor immunity.
    Frontiers in Immunology 07/2013; 4:190. DOI:10.3389/fimmu.2013.00190
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