Interleukin 6 Present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells

Kampan, N, Madondo, M, McNally, O, Stephens, A, Quinn, M and Plebanski, M 2017, 'Interleukin 6 Present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells', Frontiers in Immunology, vol. 8, no. NOV, pp. 1-14.


Document type: Journal Article
Collection: Journal Articles

Title Interleukin 6 Present in inflammatory ascites from advanced epithelial ovarian cancer patients promotes tumor necrosis factor receptor 2-expressing regulatory T cells
Author(s) Kampan, N
Madondo, M
McNally, O
Stephens, A
Quinn, M
Plebanski, M
Year 2017
Journal name Frontiers in Immunology
Volume number 8
Issue number NOV
Start page 1
End page 14
Total pages 14
Publisher Frontiers Research Foundation
Abstract Background: Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs. Methods: Ascites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-beta, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2(+) Tregs and TNFR2(-) Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC. Results: High levels of immunosuppressive (sTNFR2, IL-10, and TGF-beta) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4(+)CD25(hi)FoxP(3+) Tregs, resulting in an increased TNFR2(+) Treg/effector T cell ratio. Furthermore, TNFR2(+) Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2(+) Treg frequency was inversely correlated with interferon-gamma (IFN-gamma) production by effector T ce
Subject Medical Microbiology not elsewhere classified
Immunology not elsewhere classified
Keyword(s) Effector T cells
Epithelial ovarian cancer
FoxP3
Inflammation
Interleukin 6
Malignant ascites
Regulatory T cells
Tumour necrosis factor 2
DOI - identifier 10.3389/fimmu.2017.01482
Copyright notice © 2017 Kampan, Madondo, McNally, Stephens, Quinn and Plebanski, Open Access distributed under the terms of the Creative Commons Attribution License (CC BY).
ISSN 1664-3224
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