CD4+CD25+ T Regulatory Cells Dominate Multiple Immune Evasion Mechanisms in Early but Not Late Phases of Tumor Development in a B Cell Lymphoma Model

Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2007; 178(11):6840-8. DOI: 10.4049/jimmunol.178.11.6840
Source: PubMed

ABSTRACT Tumors use a complex set of direct and indirect mechanisms to evade the immune system. Naturally arising CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells have been implicated recently in tumor immune escape mechanism, but the relative contribution of these cells to overall tumor progression compared with other immune evasion mechanisms remains to be elucidated. Using the A20 B cell lymphoma as a transplantable tumor model, we demonstrate that this tumor employs multiple direct (expression of immunoinhibitory molecule PD-L1, IDO, and IL-10, and lack of expression of CD80 costimulatory molecule) and indirect (down-regulation of APC function and induction of Treg cells) immune evasion mechanisms. Importantly, Treg cells served as the dominant immune escape mechanism early in tumor progression because the physical elimination of these cells before tumor challenge resulted in tumor-free survival in 70% of mice, whereas their depletion in animals with established tumors had no therapeutic effect. Therefore, our data suggest that Treg cells may serve as an important therapeutic target for patients with early stages of cancer and that more vigorous combinatorial approaches simultaneously targeting multiple immune evasion as well as immunosurveillance mechanisms for the generation of a productive immune response against tumor may be required for effective immunotherapy in patients with advanced disease.

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    • "T regulatory cells (Tregs), a subset of CD4+ cells profoundly influence the immune system in tumor bearing mice, by suppressing both innate and adaptive arms of the immune system [53]. Activation of Tregs is an evasion mechanism imparted by the tumors on the host to escape the immune system [54]. Tregs express several markers like CD25, GITR, FR4 etc, and the most reliable marker is FoxP3. "
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    ABSTRACT: Two-deoxy-D-glucose (2-DG), an inhibitor of glycolysis differentially enhances the radiation and chemotherapeutic drug induced cell death in cancer cells in vitro, while the local tumor control (tumor regression) following systemic administration of 2-DG and focal irradiation of the tumor results in both complete (cure) and partial response in a fraction of the tumor bearing mice. In the present studies, we investigated the effects of systemically administered 2-DG and focal irradiation of the tumor on the immune system in Ehrlich ascites tumor (EAT) bearing Strain ''A'' mice. Markers of different immune cells were analyzed by immune-flow cytometry and secretary cytokines by ELISA, besides monitoring tumor growth. Increase in the expression of innate (NK and monocytes) and adaptive CD4 + cells, and a decrease in B cells (CD19) have been observed after the combined treatment, suggestive of activation of anti-tumor immune response. Interestingly, immature dendritic cells were found to be down regulated, while their functional markers CD86 and MHC II were up regulated in the remaining dendritic cells following the combination treatment. Similarly, decrease in the CD4 + nave cells with concomitant increase in activated CD4 + cells corroborated the immune activation. Further, a shift from Th2 and Th17 to Th1 besides a decrease in inflammatory cytokines was also observed in the animals showing complete response (cure; tumor free survival). This shift was also complimented by respective antibody class switching followed by the combined treatment. The immune activation or alteration in the homeostasis favoring antitumor immune response may be due to depletion in T regulatory cells (CD4 + CD25 + FoxP3 +). Altogether, these results suggest that early differential immune activation is responsible for the heterogenous response to the combined treatment. Taken together, these studies for the first time provided insight into the additional mechanisms underlying radio-sensitization by 2-DG in vivo by unraveling its potential as an immune-modulator besides direct effects on the tumor. Copyright: ß 2014 Farooque et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper as figures and its Supporting Information files. Funding: This work was supported by grants INM-301 and INM-311 from Defence Research and Development Organization (DRDO), Government of India. AF was recipient of a fellowship from Indian Council of Medical Research (ICMR), Government of India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
    PLoS ONE 09/2014; 9(9):1-16. DOI:10.1371/journal.pone.0108131 · 3.23 Impact Factor
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    • "This finding is partly consistent with previous reports, which suggest that tumors expressing high IDO had decreased numbers of tumor-infiltrating lymphocytes or increased numbers of FOXP3+ regulatory T cells (Treg) [7]. Also, Elpek et al. reported Treg dominated immune evasion in early stage B-cell lymphoma but not in late stage tumor [17]. Possibly, more complicated and various immune evasion mechanisms might exit in the microenvironment of advanced tumors. "
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    ABSTRACT: Background Regulation of tumor microenvironment is closely involved in the prognosis of Hodgkin lymphoma (HL). Indoleamine 2,3-dioxygenase (IDO) is an enzyme acting as immune modulator through suppression of T-cell immunity. This study aims to investigate role of IDO in the microenvironment of HL. Methods A total of 121 cases of HL were enrolled to do immunohistochemistry for IDO, CD163, CD68, CD4, CD8, and FoxP3. Positivity was evaluated from area fractions or numbers of positive cells using automated image analyzer. Correlations between IDO expression and various cellular infiltrates and clinicopathologic parameters were examined and survival analyses were performed. Results IDO was expressed in histiocytes, dendritic cells and some endothelial cells with variable degrees, but not in tumor cells. IDO positive cells were more frequently found in mixed cellularity type than other histologic types, and in cases with EBV+, high Ann Arbor stages, B symptoms, and high IPS (all p < 0.05). High IDO expression was associated with inferior survival (p < 0.001) and reflects an independent prognostic factor in nodular sclerosis HL. Conclusions This is the first study suggesting that IDO is the principle immunomodulator and is involved to adverse clinical outcomes of HL.
    BMC Cancer 05/2014; 14(1):335. DOI:10.1186/1471-2407-14-335 · 3.36 Impact Factor
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    • "Initially the immune system is able to protect the host against tumor development through immunosurveillance, which inadvertently leads to immune evasion by progression through three stages of immunoediting; elimination, equilibrium, escape [56-58]. There are several strategies that tumor cells employ during immune evasion, some of which include MHC class I structural alterations/downregulation [59, 60], mutations of Fas or TRAIL [61, 62], and inhibition of T cell receptors and/or development of Treg [63, 64]. Many of the same mechanisms are used by undifferentiated pluripotent stem cells, however, clinical transplantations would involve differentiated progenies that do not share these characteristics, and therefore additional steps need to be taken to ensure reduced immunogenicity after transplantation. "
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    ABSTRACT: One aim of stem cell-based therapy is to utilize pluripotent stem cells (PSCs) as a supplementary source of cells to repair or replace tissues or organs that have ceased to function due to severe tissue damage. However, PSC-based therapy requires extensive research to ascertain if PSC derivatives are functional without the risk of tumorigenicity, and also do not engender severe immune rejection that threatens graft survival and function. Recently, the suitability of induced pluripotent stem cells applied for patient-tailored cell therapy has been questioned since the discovery of several genetic and epigenetic aberrations during the reprogramming process. Hence, it is crucial to understand the effect of these abnormalities on the immunogenicity and survival of PSC grafts. As induced PSC-based therapy represents a hallmark for the potential solution to prevent and arrest immune rejection, this review also summarizes several up-to-date key findings in the field.
    Current Stem Cell Research & Therapy 10/2013; 9(1). DOI:10.2174/1574888X113086660068 · 2.21 Impact Factor
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