Functional Plasticity of Antigen-Specific Regulatory T Cells in Context of Tumor

Cancer Immunotherapy Group, Section of Immunobiology, Department of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
The Journal of Immunology (Impact Factor: 4.92). 03/2011; 186(8):4557-64. DOI: 10.4049/jimmunol.1003797
Source: PubMed


Although polyclonal regulatory T cells (Tregs) that once expressed Foxp3 (ex-Tregs) derived from Foxp3(+) Tregs have been described in homeostatic and autoimmune settings, little is known regarding the influence of the tumor environment on ex-Treg development. After adoptive transfer of HY-specific green Tregs (peripheral or thymic) to Rag2(-/-) B6 female mice bearing syngeneic HY-expressing MB49 tumors, a significant fraction rapidly lost expression of Foxp3. On the second transfer to a Rag2(-/-) B6 male environment, these ex-Tregs expanded strongly, whereas Tregs that maintained expression of Foxp3 expression did not. Both FACS and quantitative real-time-PCR analysis revealed that ex-Tregs upregulated genes characteristic of a Th1 effector-memory phenotype including IFN-γ and downregulated a panel of Treg-specific genes. Peripheral HY-specific green Tregs were adoptively transferred to Rag2(-/-) B6 male mice, to dissect the factors regulating ex-Treg differentiation. Development of ex-Tregs was more efficient in the mesenteric lymph node (mLN) than peripheral lymph node environment, correlating with a much greater level of IL-6 mRNA in mLN. In addition, the preferential development of ex-Tregs in mLN was significantly impaired by cotransfer of HY-specific naive CD4 T cells. Collectively, our study not only demonstrates the plasticity of Ag-specific Tregs in the context of the tumor environment, but also defines key molecular and cellular events that modulate ex-Treg differentiation.

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Available from: Caroline Addey, Mar 12, 2014
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    • "This highlights the importance of using well-defined and universally accepted parameters to identify regulatory populations, as well as including functional analysis of regulatory activity, to obtain the most accurate reflection of how regulatory responses are being affected by immunotherapy. This is especially important considering the plasticity of T cell function, where an effector cell can gain suppressive activity (and vice-versa) depending on the immune context (Bluestone et al., 2009; Addey et al., 2011). While immune monitoring by its nature is only a snapshot in time of this plasticity, it emphasizes that a comprehensive phenotypic and functional analysis will help provide the most accurate interpretation of that moment in time. "
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    ABSTRACT: While immune monitoring of tumor immunotherapy often focuses on the generation of productive Th1-type inflammatory immune responses, the importance of regulatory immune responses is often overlooked, despite the well-documented effects of regulatory immune responses in suppressing anti-tumor immunity. In a variety of malignancies, the frequency of regulatory cell populations has been shown to correlate with disease progression and a poor prognosis, further emphasizing the importance of characterizing the effects of immunotherapy on these populations. This review focuses on the role of suppressive immune populations (regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages) in inhibiting anti-tumor immunity, how these populations have been used in the immune monitoring of clinical trials, the prognostic value of these responses, and how the monitoring of these regulatory responses can be improved in the future.
    Frontiers in Oncology 05/2013; 3:109. DOI:10.3389/fonc.2013.00109
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    • "Naturally occurring activated Tregs, ready to exert their suppressive activities, are defined as CD4+CD25hiFoxp3+ T cells [16]. The definition of Tregs using multiparametric FACS analysis according to the CD4/CD25/Foxp3 phenotype allows additional functional markers to be combined and the direct ex vivo profiling of these cells, which is crucial because of the functional heterogeneity and the high lineage plasticity of Tregs [1, 17, 18]. "
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    ABSTRACT: The frequency and function of regulatory T cells (Tregs) were studied in stage II–III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low-dose interleukin-2 (IL-2). Tregs were analyzed in the lymph nodes (LNs) of stage III patients who were undergoing complete lymph node dissection and in peripheral blood mononuclear cells (PBMCs) collected before vaccination and at different time points during the vaccination period. The LNs of the vaccinated patients, which were surgically removed after two rounds of vaccination and one dose of CTX, displayed a low frequency of Tregs and a less immunosuppressive environment compared with those of the untreated patients. The accurate time-course analysis of the PBMCs of patients enrolled in the vaccination arm indicated a limited and transient modulation in the frequencies of Tregs in PBMCs collected after low-dose CTX administration and a strong Treg boost in those PBMCs collected after low-dose IL-2 administration. However, a fraction of the IL-2-boosted Tregs was functionally modulated to a Th-1-like phenotype in the vaccinated patients. Moreover, low-dose IL-2 promoted the concomitant expansion of conventional activated CD4+ T cells. Despite the amplification of Tregs, IL-2 administration maintained or further increased the number of antigen-specific CD8+ T cells that were induced by vaccination as demonstrated by the ex vivo human leukocyte antigen-multimer staining and IFN-γ ELISpot assays. Our study suggests that the use of CTX as a Treg modulator should be revised in terms of the administration schedule and of patients who may benefit from this drug treatment. Despite the Treg expansion that was observed in this study, low-dose IL-2 is not detrimental to the functional activities of vaccine-primed CD8+ T cell effectors when used in the inflammatory environment of vaccination. Electronic supplementary material The online version of this article (doi:10.1007/s00262-013-1397-7) contains supplementary material, which is available to authorized users.
    Cancer Immunology and Immunotherapy 04/2013; 62(5). DOI:10.1007/s00262-013-1397-7 · 3.94 Impact Factor
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    • "Whether Treg cells recognize a specific tumor antigen and suppress tumor antigen-specific immune responses is an important issue to further understand the involvement of Treg cells in tumor immunity. Importance of specific antigens in the development and activation of Treg cells have previously been shown [5], [6], [7]. However, model antigens and T cells from model antigen-specific TCR transgenic mice are used to simplify the system. "
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    ABSTRACT: MUC1 transgenic (MUC1.Tg) mice have widely been used as model recipients of cancer immunotherapy with MUC1. Although MUC1.Tg mice have previously been shown to be immunologically tolerant to MUC1, the involvement of regulatory T (Treg) cells in this phenotype remains unclear. Here, we showed that numbers of Treg cells in MUC1-expressing tumors were greater in MUC1.Tg mice than in control C57BL/6 (B6) mice, and that the growth of tumor cells expressing MUC1, but not that of control cells, in MUC1. Tg mice was faster than in B6 mice. The MUC1.Tg mice appeared to develop MUC1-specific peripheral tolerance, as transferred MUC1-specific T cells were unable to function in MUC1.Tg mice but were functional in control B6 mice. The suppressive function of CD4(+)CD25(high) cells from MUC1.Tg mice was more potent than that of cells from control B6 mice when Treg cell activity against MUC1-specific T cells was compared in vitro. Therefore, the enhanced growth of MUC1-expressing tumor cells in MUC1.Tg mice is likely due to the presence of MUC1-specific Treg cells.
    PLoS ONE 09/2012; 7(9):e44770. DOI:10.1371/journal.pone.0044770 · 3.23 Impact Factor
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