Skip to main content
Top
Published in: Cancer Immunology, Immunotherapy 1/2015

01-01-2015 | Original Article

Cytokine production in peripheral blood cells of patients with differentiated thyroid cancer: elevated Th2/Th9 cytokine production before and reduced Th2 cytokine production after radioactive iodine therapy

Authors: Snezana Zivancevic Simonovic, Olgica Mihaljevic, Ivana Majstorovic, Predrag Djurdjevic, Irena Kostic, Olivera Milosevic Djordjevic, Ljiljana Mijatovic Teodorovic

Published in: Cancer Immunology, Immunotherapy | Issue 1/2015

Login to get access

Abstract

Cytokines play a key role in the regulation of cells of the immune system and also have been implicated in the pathogenesis of malignant diseases. The aim of this study was to evaluate cytokine profiles in patients with differentiated thyroid cancer (DTC) before and 7 days after radioactive iodine (131-I) therapy. Cytokine levels were determined in supernatants obtained from phytohemagglutinin-stimulated whole blood cultures of 13 patients with DTC and 13 control subjects. The concentrations of selected cytokines: Th1—interferon gamma (IFN-γ), interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α); Th2—interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 13 (IL-13) and interleukin 10 (IL-10); Th9—interleukin-9 (IL-9); and Th17—interleukin 17 (IL-17A) were measured using multiplex cytokine detection systems for Human Th1/Th2/Th9/Th17/Th22. We have shown that peripheral blood cells of DTC patients produce significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. The 131-I therapy led to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Despite this, the calculated cytokine ratios (Th1/Th2) in DTC patients before and 7 days after 131-I therapy were not different from those in healthy subjects. DTC patients have significantly higher concentrations of Th2/Th9 cytokines (IL-5, IL-13 and IL-9) than control subjects. There is no influence of hypothyroidism or stage of disease on cytokine production in DTC patients before 131-I therapy. The radioactive 131-I therapy leads to reduced secretion of Th2 cytokines (IL-4, IL-5 and IL-13). Additional studies are needed to determine the significance of these findings.
Literature
1.
go back to reference Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295:2164–2167PubMedCrossRef Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295:2164–2167PubMedCrossRef
2.
go back to reference Schlumberger M, Sherman SI (2012) Endocrine tumors: approach to the patient with advanced differentiated thyroid cancer. Eur J Endocrinol 166:5–11PubMedCrossRef Schlumberger M, Sherman SI (2012) Endocrine tumors: approach to the patient with advanced differentiated thyroid cancer. Eur J Endocrinol 166:5–11PubMedCrossRef
3.
go back to reference Cooper DS, Doherty GM, Haugen BR et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:1167–1214PubMedCrossRef Cooper DS, Doherty GM, Haugen BR et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:1167–1214PubMedCrossRef
4.
go back to reference Luster M, Clarke SE, Dietlein M et al (2008) Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 35:1941–1959PubMedCrossRef Luster M, Clarke SE, Dietlein M et al (2008) Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 35:1941–1959PubMedCrossRef
5.
go back to reference Punnonen R, Teisala K, Kuoppala T et al (1998) Cytokine production profiles in the peritoneal fluids of patients with malignant or benign gynecologic tumors. Cancer 83:788–796PubMedCrossRef Punnonen R, Teisala K, Kuoppala T et al (1998) Cytokine production profiles in the peritoneal fluids of patients with malignant or benign gynecologic tumors. Cancer 83:788–796PubMedCrossRef
6.
go back to reference Clerici M, Shearer GM, Clerici E (1998) Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias: time to consider the TH1/TH2 paradigm. J Natl Cancer Inst 90:261–263PubMedCrossRef Clerici M, Shearer GM, Clerici E (1998) Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias: time to consider the TH1/TH2 paradigm. J Natl Cancer Inst 90:261–263PubMedCrossRef
7.
go back to reference Budhu A, Wang XW (2006) The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 80:1197–1213PubMedCrossRef Budhu A, Wang XW (2006) The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 80:1197–1213PubMedCrossRef
8.
go back to reference Bodelon C, Polley MY, Kemp TJ et al (2013) Circulating levels of immune and inflammatory markers and long versus short survival in early-stage lung cancer. Ann Oncol 24:2073–2079PubMedCentralPubMedCrossRef Bodelon C, Polley MY, Kemp TJ et al (2013) Circulating levels of immune and inflammatory markers and long versus short survival in early-stage lung cancer. Ann Oncol 24:2073–2079PubMedCentralPubMedCrossRef
9.
go back to reference Ellyard JI, Simson L, Parish CR (2007) Th2-mediated anti-tumour immunity: friend or foe? Tissue Antigens 70(1):1–11PubMedCrossRef Ellyard JI, Simson L, Parish CR (2007) Th2-mediated anti-tumour immunity: friend or foe? Tissue Antigens 70(1):1–11PubMedCrossRef
10.
go back to reference Baier PK, Wolff-Vorbeck G, Eggstein S et al (2005) Cytokine expression in colon carcinoma. Anticancer Res 25:2135–2139PubMed Baier PK, Wolff-Vorbeck G, Eggstein S et al (2005) Cytokine expression in colon carcinoma. Anticancer Res 25:2135–2139PubMed
11.
go back to reference Mocellin S, Provenzano M, Rossi CR et al (2003) Use of quantitative real-time PCR to determine immune cell density and cytokine gene profile in the tumor microenvironment. J Immunol Methods 280:1–11PubMedCrossRef Mocellin S, Provenzano M, Rossi CR et al (2003) Use of quantitative real-time PCR to determine immune cell density and cytokine gene profile in the tumor microenvironment. J Immunol Methods 280:1–11PubMedCrossRef
12.
go back to reference Ikeguchi M, Matsumoto S, Murakami D et al (2004) Gene expression levels of cytokines in peritoneal washings from patients with gastric cancer. Tumour Biol 25:117–121PubMedCrossRef Ikeguchi M, Matsumoto S, Murakami D et al (2004) Gene expression levels of cytokines in peritoneal washings from patients with gastric cancer. Tumour Biol 25:117–121PubMedCrossRef
13.
go back to reference Montero AJ, Diaz-Montero CM, Millikan RE et al (2009) Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon: association of pretreatment serum levels with survival. Ann Oncol 20:1682–1687PubMedCrossRef Montero AJ, Diaz-Montero CM, Millikan RE et al (2009) Cytokines and angiogenic factors in patients with metastatic renal cell carcinoma treated with interferon: association of pretreatment serum levels with survival. Ann Oncol 20:1682–1687PubMedCrossRef
14.
go back to reference Özata M, Ergun H, Öziflik G et al (2000) Effect of radioiodine therapy on several hematological and immune parameters in patients with differentiated thyroid carcinoma. Turk J Endocrinol Metab 2:45–50 Özata M, Ergun H, Öziflik G et al (2000) Effect of radioiodine therapy on several hematological and immune parameters in patients with differentiated thyroid carcinoma. Turk J Endocrinol Metab 2:45–50
15.
go back to reference Mardente S, Lenti L, Lococo E et al (2005) Phenotypic and functional characterization of lymphocytes in autoimmune thyroiditis and in papillary carcinoma. Anticancer Res 25:2483–2488PubMed Mardente S, Lenti L, Lococo E et al (2005) Phenotypic and functional characterization of lymphocytes in autoimmune thyroiditis and in papillary carcinoma. Anticancer Res 25:2483–2488PubMed
16.
go back to reference Xiang GA, Chen KY, Wang NH et al (2010) Immunological influence of iodine-125 implantation in patients with hepatocellular carcinoma resection. Nan Fang Yi Ke Da Xue Xue Bao 30:292–294PubMed Xiang GA, Chen KY, Wang NH et al (2010) Immunological influence of iodine-125 implantation in patients with hepatocellular carcinoma resection. Nan Fang Yi Ke Da Xue Xue Bao 30:292–294PubMed
17.
go back to reference Jones BM, Kwok CCH, Kung AWC (1999) Effect of radioactive iodine therapy on cytokine production in Graves’ disease: transient increases in interleukin-4 (IL-4), IL-6, IL-10, and tumor necrosis factor-α, with longer term increases in interferon-γ production. J Clin Endocrinol Metab 84:4106–4110PubMed Jones BM, Kwok CCH, Kung AWC (1999) Effect of radioactive iodine therapy on cytokine production in Graves’ disease: transient increases in interleukin-4 (IL-4), IL-6, IL-10, and tumor necrosis factor-α, with longer term increases in interferon-γ production. J Clin Endocrinol Metab 84:4106–4110PubMed
18.
go back to reference Heney D, Whicher JT (1995) Factors affecting the measurement of cytokines in biological fluids: implications for their clinical measurement. Ann Clin Biochem 32:358–368PubMedCrossRef Heney D, Whicher JT (1995) Factors affecting the measurement of cytokines in biological fluids: implications for their clinical measurement. Ann Clin Biochem 32:358–368PubMedCrossRef
19.
20.
go back to reference Stassi G, Todaro M, Zerilli M et al (2003) Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res 63:6784–6790PubMed Stassi G, Todaro M, Zerilli M et al (2003) Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res 63:6784–6790PubMed
21.
go back to reference Bais AG, Beckmann I, Lindemans J et al (2005) A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions. J Clin Pathol 58:1096–1100PubMedCentralPubMedCrossRef Bais AG, Beckmann I, Lindemans J et al (2005) A shift to a peripheral Th2-type cytokine pattern during the carcinogenesis of cervical cancer becomes manifest in CIN III lesions. J Clin Pathol 58:1096–1100PubMedCentralPubMedCrossRef
22.
go back to reference Kulbe H, Chakravarty P, Leinster DA et al (2012) A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res 72:66–75PubMedCentralPubMedCrossRef Kulbe H, Chakravarty P, Leinster DA et al (2012) A dynamic inflammatory cytokine network in the human ovarian cancer microenvironment. Cancer Res 72:66–75PubMedCentralPubMedCrossRef
23.
go back to reference Duramad P, McMahon CW, Hubbard A et al (2004) Flow cytometric detection of intracellular Th1/Th2 cytokines using whole blood: validation of immunologic biomarker for use in epidemiologic studies. Cancer Epidemiol Biomark Prev 13:1452–1458 Duramad P, McMahon CW, Hubbard A et al (2004) Flow cytometric detection of intracellular Th1/Th2 cytokines using whole blood: validation of immunologic biomarker for use in epidemiologic studies. Cancer Epidemiol Biomark Prev 13:1452–1458
24.
go back to reference Ito N, Nakamura H, Metsugi H et al (2001) Dissociation between T helper type 1 and type 2 differentiation and cytokine production in tumor-infiltrating lymphocytes in patients with lung cancer. Surg Today 31:390–394PubMedCrossRef Ito N, Nakamura H, Metsugi H et al (2001) Dissociation between T helper type 1 and type 2 differentiation and cytokine production in tumor-infiltrating lymphocytes in patients with lung cancer. Surg Today 31:390–394PubMedCrossRef
26.
go back to reference Nevala WK, Vachon CM, Leontovich AA et al (2009) Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res 15:1931–1939PubMedCentralPubMedCrossRef Nevala WK, Vachon CM, Leontovich AA et al (2009) Evidence of systemic Th2-driven chronic inflammation in patients with metastatic melanoma. Clin Cancer Res 15:1931–1939PubMedCentralPubMedCrossRef
27.
go back to reference Smyth GP, Stapleton PP, Barden CB et al (2003) Renal cell carcinoma induces prostaglandin E2 and T-helper type 2 cytokine production in peripheral blood mononuclear cells. Ann Surg Oncol 10:455–462PubMedCrossRef Smyth GP, Stapleton PP, Barden CB et al (2003) Renal cell carcinoma induces prostaglandin E2 and T-helper type 2 cytokine production in peripheral blood mononuclear cells. Ann Surg Oncol 10:455–462PubMedCrossRef
29.
go back to reference Fujisawa T, Terada A, Atsuta J et al (1997) IL-5 as a strong secretagogue for human eosinophils. Int Arch Allergy Immunol 114:81–83PubMedCrossRef Fujisawa T, Terada A, Atsuta J et al (1997) IL-5 as a strong secretagogue for human eosinophils. Int Arch Allergy Immunol 114:81–83PubMedCrossRef
30.
go back to reference Gatault S, Legrand F, Delbeke M et al (2012) Involvement of eosinophils in the anti-tumor response. Cancer Immunol Immunother 61:1527–1534PubMedCrossRef Gatault S, Legrand F, Delbeke M et al (2012) Involvement of eosinophils in the anti-tumor response. Cancer Immunol Immunother 61:1527–1534PubMedCrossRef
31.
go back to reference Kataoka S, Konishi Y, Nishio Y et al (2004) Antitumor activity of eosinophils activated by IL-5 and eotaxin against hepatocellular carcinoma. DNA Cell Biol 23:549–560PubMedCrossRef Kataoka S, Konishi Y, Nishio Y et al (2004) Antitumor activity of eosinophils activated by IL-5 and eotaxin against hepatocellular carcinoma. DNA Cell Biol 23:549–560PubMedCrossRef
32.
go back to reference Simson L, Ellyard JI, Dent LA et al (2007) Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J Immunol 178:4222–4229PubMedCrossRef Simson L, Ellyard JI, Dent LA et al (2007) Regulation of carcinogenesis by IL-5 and CCL11: a potential role for eosinophils in tumor immune surveillance. J Immunol 178:4222–4229PubMedCrossRef
33.
go back to reference Mattes J, Hulett M, Xie W et al (2003) Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process. J Exp Med 197:387–393PubMedCentralPubMedCrossRef Mattes J, Hulett M, Xie W et al (2003) Immunotherapy of cytotoxic T cell-resistant tumors by T helper 2 cells: an eotaxin and STAT6-dependent process. J Exp Med 197:387–393PubMedCentralPubMedCrossRef
34.
go back to reference Modesti A, Masuelli L, Modica A et al (1993) Ultrastructural evidence of the mechanisms responsible for interleukin-4-activated rejection of a spontaneous murine adenocarcinoma. Int J Cancer 53:988–993PubMedCrossRef Modesti A, Masuelli L, Modica A et al (1993) Ultrastructural evidence of the mechanisms responsible for interleukin-4-activated rejection of a spontaneous murine adenocarcinoma. Int J Cancer 53:988–993PubMedCrossRef
35.
go back to reference Musiani P, Allione A, Modica A et al (1996) Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. Lab Invest 74:146–157PubMed Musiani P, Allione A, Modica A et al (1996) Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. Lab Invest 74:146–157PubMed
36.
go back to reference Tepper RI, Coffman RL, Leder P (1992) An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science 257:548–551PubMedCrossRef Tepper RI, Coffman RL, Leder P (1992) An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science 257:548–551PubMedCrossRef
37.
go back to reference Lebel-Binay S, Laguerre B, Quintin-Colonna F et al (1995) Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin-13. Eur J Immunol 25:2340–2348PubMedCrossRef Lebel-Binay S, Laguerre B, Quintin-Colonna F et al (1995) Experimental gene therapy of cancer using tumor cells engineered to secrete interleukin-13. Eur J Immunol 25:2340–2348PubMedCrossRef
38.
go back to reference Terabe M, Matsui S, Noben-Trauth N et al (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515–520PubMedCrossRef Terabe M, Matsui S, Noben-Trauth N et al (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515–520PubMedCrossRef
39.
go back to reference Ma HL, Whitters MJ, Jacobson BA et al (2004) Tumor cells secreting IL-13 but not IL-13Ralpha2 fusion protein have reduced тumorigenicity in vivo. Int Immunol 16:1009–1017PubMedCrossRef Ma HL, Whitters MJ, Jacobson BA et al (2004) Tumor cells secreting IL-13 but not IL-13Ralpha2 fusion protein have reduced тumorigenicity in vivo. Int Immunol 16:1009–1017PubMedCrossRef
40.
go back to reference Li H, Rostami A (2010) IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity. J Neuroimmune Pharmacol 5:198–209PubMedCrossRef Li H, Rostami A (2010) IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity. J Neuroimmune Pharmacol 5:198–209PubMedCrossRef
41.
go back to reference Purwar R, Schlapbach C, Xiao S et al (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18:1248–1253PubMedCrossRef Purwar R, Schlapbach C, Xiao S et al (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18:1248–1253PubMedCrossRef
42.
go back to reference Valli E, Sterle HA, Méndez-Huergo S et al (2013) Regulatory T cells mediate immunosupression induced by experimental hypothyroidism (P1215). J Immunol 190:188.10 (abstract) Valli E, Sterle HA, Méndez-Huergo S et al (2013) Regulatory T cells mediate immunosupression induced by experimental hypothyroidism (P1215). J Immunol 190:188.10 (abstract)
43.
go back to reference Nieto P, Peñaloza H, Salazar F et al (2014) Gestational hypothyroidism in mice makes female offspring more resistant to pneumococcal pneumonia (MUC5P.869). J Immunol 192:134.12 (abstract) Nieto P, Peñaloza H, Salazar F et al (2014) Gestational hypothyroidism in mice makes female offspring more resistant to pneumococcal pneumonia (MUC5P.869). J Immunol 192:134.12 (abstract)
44.
go back to reference Botella-Carretero JI, Prados A, Manzano L et al (2005) The effects of thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with differentiated thyroid carcinoma before and during thyroxine withdrawal. Eur J Endocrinol 153:223–230PubMedCrossRef Botella-Carretero JI, Prados A, Manzano L et al (2005) The effects of thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with differentiated thyroid carcinoma before and during thyroxine withdrawal. Eur J Endocrinol 153:223–230PubMedCrossRef
45.
go back to reference Barsegian V, Müller SP, Horn PA et al (2011) Lymphocyte function following radioiodine therapy in patients with thyroid carcinoma. Nuklearmedizin 50:195–203PubMedCrossRef Barsegian V, Müller SP, Horn PA et al (2011) Lymphocyte function following radioiodine therapy in patients with thyroid carcinoma. Nuklearmedizin 50:195–203PubMedCrossRef
Metadata
Title
Cytokine production in peripheral blood cells of patients with differentiated thyroid cancer: elevated Th2/Th9 cytokine production before and reduced Th2 cytokine production after radioactive iodine therapy
Authors
Snezana Zivancevic Simonovic
Olgica Mihaljevic
Ivana Majstorovic
Predrag Djurdjevic
Irena Kostic
Olivera Milosevic Djordjevic
Ljiljana Mijatovic Teodorovic
Publication date
01-01-2015
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 1/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-014-1619-7

Other articles of this Issue 1/2015

Cancer Immunology, Immunotherapy 1/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine