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.
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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ABSTRACT: The aim of the present study was to explore the effect of hypoxia on ovarian cancer. A total of 6 samples were analyzed: SKOV3‑IP cells (ovarian cancer cell line); SKOV3‑IP and regulatory T (Treg) cells; SKOV3‑IP and cytotoxic T lymphocytes (CTLs); SKOV3‑IP and natural killer (NK) cells; SKOV3‑IP co-cultured with CTLs and Treg cells; and SKOV3‑IP co-cultured with Treg cells and NK cells. The expression of indoleamine 2,3‑dioxygenase (IDO) was detected by reverse transcription-polymerase chain reaction (RT‑PCR) and western blot analysis. An enzyme‑linked immunosorbent assay (ELISA) was used to detect the concentration of transforming growth factor‑β (TGF‑β), interferon‑γ (IFN‑γ), interleukin‑2 (IL‑2), interleukin‑10 (IL‑10), and perforin. Moreover, ovarian cancer cell apoptosis and invasive ability were examined using flow cytometry and a Transwell chamber assay. IDO expression was significantly reduced in hypoxia and enhanced by Treg cells. Treg cells inhibited the IL‑2, IFN‑γ and perforin secretion, and significantly (P<0.05) increased the IL‑10 and TGF‑β levels. The effects of Treg cells were enhanced with prolongation of the cell exposure to hypoxic conditions. In addition, Treg cells attenuated the promotive effect of CTLs and NK cells on cancer cell apoptosis. In addition, Treg cells significantly increased the SKOV3‑IP invasive ability (P=0.00109) under hypoxic conditions. Our results suggest that IDO and Treg cells may serve as important therapeutic targets for patients with ovarian cancer.Molecular Medicine Reports 11/2014; 11(3). DOI:10.3892/mmr.2014.2893 · 1.48 Impact Factor
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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 · 3.53 Impact Factor
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ABSTRACT: Immunotherapy for the treatment of cancer is rapidly evolving from therapies that globally and non-specifically simulate the immune system to more targeted activation of individual components of the immune system. The net result of this targeted approach is decreased toxicity and increased efficacy of immunotherapy. More specifically, therapies that inhibit the interaction between programmed death ligand 1 (PD-L1), present on the surface of tumor or antigen-presenting cells, and programmed death 1 (PD-1), present on the surface of activated lymphocytes, are generating much excitement and enthusiasm, even in malignancies that are not traditionally considered to be immunogenic. Herein, we review the current landscape of anti-PD-1 and anti-PD-L1 therapies in the world of oncology. We have performed a comprehensive literature search on the data available through PubMed, Medline, Scopus, the ClinicalTrials.gov registry, and abstracts from major oncology meetings in order to summarize the clinical data of anti-PD-1/PD-L1 therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.