Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2015

Open Access 01-12-2015 | Research

Regulatory T lymphocytes and transforming growth factor beta in epithelial ovarian tumors-prognostic significance

Authors: Izabela Winkler, Barbara Wilczynska, Agnieszka Bojarska-Junak, Marek Gogacz, Aneta Adamiak, Krzysztof Postawski, Dorota Darmochwal-Kolarz, Tomasz Rechberger, Jacek Tabarkiewicz

Published in: Journal of Ovarian Research | Issue 1/2015

Login to get access

Abstract

Background

Regulatory T lymphocytes (Treg) are characterized by the presence of CD4+ surface antigen. Today the transcription factor FOXP3 is considered to be the most specific marker of Treg cells. The aim of the study was to estimate the percentage of Treg in peripheral blood and the tissue of the epithelial ovarian tumor and blood serum TGF-beta concentrations and relationships between them. Moreover, the aim of the study was to answer the question whether the percentage of Treg lymphocytes affects the time of survival in patients with ovarian cancer.

Methods

The patients were divided into four groups, depending on the histopathological examination result: I – a group without any pathology within the ovaries (C; n = 20), II – a group with benign tumors (B; n = 25), III – with borderline tumors (BR; n = 11), IV – a group with cancer of the ovary (M; n = 24). The percentage of Treg lymphocytes in peripheral blood and the tissue was assessed using the flow cytometry method. TGF-beta cytokine concentration was estimated with the ELISA immunoenzymatic test. Statistical analysis of the results was conducted using the computer program Statistica 10.0PL (StatSoft, Inc).

Results

No significant differences were found in percentages of Treg lymphocytes in peripheral blood between individual groups of patients (p = 0.11). However, we observed marked differences in the tissue of malignant and non-malignant tumors between individual groups of patients (p = 0.003). The analysis with the post hoc test revealed significantly higher TGF-beta concentration in the group of women with malignant tumors. Moreover, no relationship was found between TGF-beta concentration and the percentage of Treg cells in peripheral blood and tumors of the ovary. No correlation was found between the percentage of Treg lymphocytes in peripheral blood (p = 0.4) and the tissue of ovarian tumors (p = 0.3) and the time of survival of patients with ovarian cancer.

Conclusions

The recruitment of Treg lymphocytes toward the tumor is one of the mechanisms of escape of neoplasm from the response of the immune system. The percentage of Treg lymphocytes in peripheral blood and the neoplastic tissue does not influence the time of survival of patients with ovarian cancer.
Literature
1.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;n155(3):h1151–64.
2.
Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol. 2005;6:331–7.PubMedCrossRef
3.
4.
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4 + CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.PubMedCrossRef
5.
6.
7.
Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med. 2001;194:629–44.PubMedCentralPubMedCrossRef
8.
Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, et al. CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med. 2002;196:237–46.PubMedCentralPubMedCrossRef
9.
Andersson J, Tran DQ, Pesu M, Davidson TS, et al. CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med. 2008;205(9):1975–81.PubMedCentralPubMedCrossRef
10.
Lin Y, Kikuchi S, Tamakoshi A, et al. Serum transforming growth factor-beta1 levels and pancreatic cancer risk: a nested case–control study (Japan). Cancer Causes Control. 2006;17:1077–82.PubMedCrossRef
11.
12.
Scully RE, Young RH, Clement PB. Tumors of ovary, mal developed gonads, fallopian tube, and broad ligament. In: Atlas of tumor pathology. Washington, DC: Armed Forces Institute of Pathology; 1998. Fascicle 23, 3 rd series.
13.
Chen VW, Ruiz B, Killeen JR, Cote’ TR, Wu XC, Correa CN. Pathology and classification of ovarian tumors. Cancer. 2003;97, 120(Suppl):2631–42.CrossRef
14.
Pettersson F. Annual report of the results of treatment in gynecological cancer. Stockholm: International Federation of Gynecology and Obstetrics; 1991.
15.
Averette HE, Janicek MF, Menck HR. The national cancer data base report on ovarian cancer. American college of surgeons commission on cancer and the american cancer society. Cancer. 1995;76:1096–103.PubMedCrossRef
16.
Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, et al. Regulatory CD4 + CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61:4766–72.PubMed
17.
Fialová A, Partlová S, Sojka L, Hromádková H, Brtnický T, Fučíková J, et al. Dynamics of T-cell infiltration during the course of ovarian cancer: the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. Int J Cancer. 2013;132, 5:1070–9.CrossRef
18.
Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann F, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169:2756–61.PubMedCrossRef
19.
Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.PubMedCrossRef
20.
Valzasina B, Piconese S, Guiducci C, Colombo MP. Tumor-induced expansion of regulatory t cells by conversion of CD4 + CD25- lymphocytes is thymus and proliferation independent. Cancer Res. 2006;66:4488–95.PubMedCrossRef
21.
Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2004;103:1755–62.PubMedCrossRef
22.
Dannull J, Su Z, Rizzieri D, Benjamin K, Yang, Coleman D, et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest. 2005;115:3623–33.PubMedCentralPubMedCrossRef
23.
Nashan B, Moore R, Amlot P, Schmid A, Abeywickrama K, Soulillou J. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet. 1997;350, 9086:1193–8.CrossRef
24.
Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, et al. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med. 1998;338, 3:161–5.CrossRef
25.
Rech A, Vonderheide R. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci. 2009;1174:99–106.PubMedCrossRef
26.
27.
Inman GJ. Switching TGF, beta from a tumor suppressor to a tumor promoter. Curr Opin Genet Dev. 2011;21(1):93–9.PubMedCrossRef
28.
Wendt MK, Tian M, Schiemann WP. Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression. Cell Tissue Res. 2012;347(1):85–101.PubMedCentralPubMedCrossRef
29.
Langenskiold M, Holmdahl L, Falk P, et al. Increased TGF-beta 1 protein expression in patients with advanced colorectal cancer. J Surg Oncol. 2008;97(5):409–15.PubMedCrossRef
30.
Liu VC, Wong LY, Jang T, et al. Tumor evasion of the immune system by converting CD4 + CD25− T cells into CD4 + CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol. 2007;178:2883–92.PubMedCrossRef
31.
Bartlett JM, Langdon SP, Scott WN, Love SB, Miller EP, Katsaros D, et al. Transforming growth factor-beta isoform expression in human ovarian tumours. Eur J Cancer. 1997;33:2397–403.PubMedCrossRef
32.
Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC. The regulation of apoptosis by activin and transforming growth factor-beta in early neoplastic and tumorigenic ovarian surface epithelium. J Clin Endocrinol Metab. 2001;86:2125–35.PubMed
33.
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5, e38.PubMedCentralPubMedCrossRef
34.
Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H. Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res. 2003;9:4404–8.PubMed
35.
Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, et al. DNA methylation controls foxp3 gene expression. Eur J Immunol. 2008;38:1654–63.PubMedCrossRef
36.
37.
Schlingensiepen H, Fischer-Blass B, Schmaus S, Ludwig S. Antisense therapeutics for tumor treatment: the TGF-beta2 inhibitor AP 12009 in clinical development against malignant tumors. Recent Res Cancer. 2009;177:137–50.CrossRef
38.
Melisi D, Ishiyama S, Sclabas G, Fleming JB, Qia Q, Tortora G, et al. LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008;4:829–40.CrossRef
39.
Søndergaard H, Skak K. IL-21: roles in immunopathology and cancer therapy. Tissue Antigens. 2009;74(6):467–79.PubMedCrossRef
40.
Dangaj D, Lanitis E, Zhao A, Joshi S, Cheng Y, Sandaltzopoulos R, et al. Novel recombinant human b7-h4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses. Cancer Res. 2013;73(15):4820–9.PubMedCentralPubMedCrossRef
41.
Chester C, Dorigo O, Berek JS, Kohrt H. Immunotherapeutic approaches to ovarian cancer treatment. J Immunother Cancer. 2015;24;3:7.CrossRef
42.
Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A, et al. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol Oncol. 2009;115(2):185–92.PubMedCrossRef
Metadata
Title
Regulatory T lymphocytes and transforming growth factor beta in epithelial ovarian tumors-prognostic significance
Authors
Izabela Winkler
Barbara Wilczynska
Agnieszka Bojarska-Junak
Marek Gogacz
Aneta Adamiak
Krzysztof Postawski
Dorota Darmochwal-Kolarz
Tomasz Rechberger
Jacek Tabarkiewicz
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2015
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-015-0164-0

Other articles of this Issue 1/2015

Journal of Ovarian Research 1/2015 Go to the issue

Research

Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids

Research

Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer

Case report

Successful live birth after transfer of blastocyst and frozen blastocyst from rescue ICSI with application of polarized light microscopy for spindle examination on unfertilized eggs

Review

MicroRNAs in ovarian function and disorders

Research

Integrative network analysis for survival-associated gene-gene interactions across multiple genomic profiles in ovarian cancer

Review

Prognostic value of circulating tumor cells and disseminated tumor cells in patients with ovarian cancer: a systematic review and meta-analysis