IL-2 and IL-12 in thyroid cancer: Clinical implication

Toral Kobawala, Kinjal Gajjar, Trupti Trivedi, Girish Patel, Nandita Ghosh

Abstract


Purpose: The roles of IL-2 and IL-12, in different malignancies have been looked for since years. But very few studies have elucidated their role in thyroid tumorigenesis. Hence, present study sought to explore their utility in thyroid cancer, mainly the papillary thyroid cancer (PTC).

Methods: A total of 67 patients with benign thyroid diseases, 106 with thyroid cancer and 67 healthy individuals were included in the study. Circulating levels of IL-2 and IL-12 were estimated by ELISA from all patients and controls. Protein expression of both interleukins was determined using immunohistochemistry. The results were statistically analysed using SPSS software.

Results: Serum IL-12 exhibited good discriminatory efficacy between patients with benign thyroid diseases and healthy individuals. IL-2 and IL-12 levels could efficiently differentiate PTC and anaplastic thyroid cancer (ATC) patients from healthy individuals. Additionally, IL-12 showed good discriminating efficacy between PTC and benign thyroid disease patients and IL-2 well discriminated ATC patients from benign thyroid diseases. IL-2 was significantly higher in patients having unilateral tumors (P=0.006) while, IL-12 was significantly higher in patients with smaller tumor size (P=0.036) and early stage disease (P=0.008). The cytokine protein expressions in benign thyroid tissues and carcinoma did not differ significantly. IL-12 expression was significantly higher in male patients (P=0.042) and unilateral tumors (P=0.031).Kaplan-Meier survival analysis revealed that nuclear IL-2 expression was able to predict disease free survival and overall survival (OS) in subgroup of PTC patients having multifocal tumors and only OS in patients having bilateral tumors. Moreover, higher IL-12 immunoreactivity was a significant predictor of shorter OS in PTC patients treated with surgery alone.

Conclusion: Serologic determination of IL-2 and IL-12 may help in validating indeterminate FNAC results and disclose diagnostic difference between benign and malignant thyroid diseases. However, a large cohort study is mandatory to establish a defined cut off for such discrimination.


Keywords


IL-2, IL-12, Thyroid tumorigenesis, Papillary thyroid cancer, Immunohistochemistry, ELISA

References


Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451-8.

Smith KA. Interleukin-2: inception, impact, and implications. Science. 1988;240:1169-76.

Wang X, Lupardus P, LaPorte SL, et al. Structural biology of shared cytokine receptors. Annu Rev Immunol. 2009;27:29-60.

Malek TR, Castro I. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 2010;33:153-65.

Liao W, Lin J-X, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38:13-25.

Azzarone B, Pottin-Clemenceau C, Krief P, et al. Are interleukin-2 and interleukin-15 tumor promoting factors for human non-hematopoietic cells? Eur Cytokine Netw. 1996;7:27-36.

Carloni G, Paterson H, Mareel M, et al. N-ras dependent revertant phenotype in human HT1080 fibrosarcoma cells is associated with loss of proliferation within normal tissues and expression of an adult membrane antigenic phenotype. Oncogene. 1989;4:873-80.

Plaisance S, Rubinstein E, Allleche A, et al. Expression of the interleukin-2 receptor on human fibroblasts and its biological significance. IntImmunol. 1992;4:739-46.

Reichert TE, Watkins S, Stanson J, et al. Endogenous IL-2 in cancer cells: a marker of cellular proliferation. J HistochemCytochem. 1998;46:603-11.

Royuela M, De Miguel MP, Bethencourt FR, et al. IL-2, its receptors, and bcl-2 and bax genes in normal, hyperplastic and carcinomatous human prostates: immunohistochemical comparative analysis. Growth Factors. 2000;18:135-46.

Nagashima N, Nakayama Y, Inoue Y, et al. Prognostic significance of the local expression of interleukin-12 in patients with advanced gastric cancer. Anticancer Res. 2008;28:1277-83.

Tatsumi T, Huang J, Gooding WE, et al. Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer Res. 2003;63:6378-86.

Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.Science. 2006;313:1960-4.

Baxevanis CN, Gritzapis AD, Papamichail M. In vivo antitumor activity of NKT cells activated by the combination of IL-12 and IL-18. J Immunol. 2003;171:2953-9.

Sugai H, Kono K, Takahashi A, et al. Characteristic alteration of monocytes with increased intracellular IL-10 and IL-12 in patients with advanced-stage gastric cancer. J Surg Res. 2004;116:277-87.

Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol. 2013;14:e218-28.

Atkins MB, Robertson MJ, Gordon M, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies.Clin Cancer Res. 1997;3(3):409-17.

Motzer RJ, Rakhit A, Schwartz LH, et al. Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res. 1998;4:1183-91.

Sangro B, Mazzolini G, Ruiz J, et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J ClinOncol. 2004;22:1389-97.

Weiss JM, Subleski JJ, Wigginton JM, et al. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert OpinBiolTher. 2007;7:1705-21.

Kobawala TP, Trivedi TI, Gajjar KK, et al. Significance of TNF-α and the adhesion molecules: L-Selectin and VCAM-1 in papillary thyroid carcinoma. J Thyroid Res. 2016;2016:17.

Kobawala TP, Trivedi TI, Gajjar KK, et al. Significance of Interleukin-6 in Papillary Thyroid Carcinoma. J Thyroid Res. 2016;2016:12.

Kobawala T, Trivedi T, Gajjar K, et al. Role of Interleukin-18 in thyroid tumorigenesis.Int J Cancer TherOncol. 2016;4(4):431.

Remmele W, Stegner H. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Der Pathologe. 1987;8: 138-40.

Agarwal A, Agrawal U, Verma S, et al. Serum Th1 and Th2 cytokine balance in patients of superficial transitional cell carcinoma of bladder pre-and post-intravesical combination immunotherapy. ImmunopharmacolImmunotoxicol. 2010;32:348-56.

Lin CC, Yin MC. Clinical significance of circulating IL-10 and fibronectin levels in hepatocellular carcinoma patients with HBV infection. BioMedicine. 2012;2:122-6.

McMillan D, Kernohan N, Flett M, et al. Interleukin 2 receptor expression and interleukin 2 localisation in human solid tumour cells in situ and in vitro: Evidence for a direct role in the regulation of tumor cell proliferation. Int J Cancer. 1995;60:766-72.

Garcia-Tunon I, Ricote M, Ruiz A, et al. Interleukin-2 and its receptor complex (α, β and γ chains) in in situ and infiltrative human breast cancer: an immunohistochemical comparative study. Breast Cancer Res. 2003;6: R1-7.

Lin W-C, Yasumura S, Suminami Y, et al. Constitutive production of IL-2 by human carcinoma cells, expression of IL-2 receptor, and tumor cell growth. J Immunol. 1995;155:4805-16.

Ridings J, Macardle P, Byard R, et al. Cytokine receptor expression by solid tumours. TherImmunol. 1995;2: 67-76.

Reichert TE, Nagashima S, Kashii Y, et al. Interleukin-2 expression in human carcinoma cell lines and its role in cell cycle progression. Oncogene. 2000;19:514-25.

Barzon L, Bonaguro R, Castagliuolo I, et al. Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase. Eur J Endocrinol. 2003;148: 73-80.

Vitale G, Lupoli G, Guarrasi R, et al. Interleukin-2 and lanreotide in the treatment of medullary thyroid cancer: in vitro and in vivo studies. J ClinEndocrinolMetab. 2013;98:E1567-74.

Tsuboi K, Miyazaki T, Nakajima M, et al. Serum interleukin-12 and interleukin-18 levels as a tumor marker in patients with esophageal carcinoma. Cancer Lett. 2004;205:207-14.

Diakowska D, Markocka-Maczka K, Grabowski K, et al. Serum interleukin-12 and interleukin-18 levels in patients with oesophageal squamous cell carcinoma. ExpOncol. 2006;28:319-22.

Moretti S, Chiarugi A, Semplici F, et al. Serum imbalance of cytokines in melanoma patients. Melanoma Res. 2001;11:395-9.

Hussein MZ, Al Fikky A, Abdel BI, et al. Serum IL-6 and IL-12 levels in breast cancer patients. Egypt J Immunol. 2004;11:165-70.

Guo Q, Shen S, Li X, et al. Inflammatory factors promote the development of colorectal cancer. Zhong Nan Da XueXueBao Yi Xue Ban. Med sciences. 2011;36(7):646-9.

Tefferi A, Vaidya R, Caramazza D, et al. A circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehensive cytokine profiling study. J ClinOncol. 2011;29:1356-63.

Marri PR, Hodge LS, Maurer MJ, et al. Prognostic significance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19:6812-9.

Salmaggi A, Eoli M, Frigerio S, et al. Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol. 2003;62:297-303.

Albulescu R, Codrici E, Popescu ID, et al. Cytokine patterns in brain tumor progression. Mediators Inflamm. 2013;2013:979748.

Kumar R, Kamdar D, Madden L, et al. Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastomamultiforme patients. Oncol Rep. 2006;15:1513-6.

Jebreel A, Mistry D, Loke D, et al. Investigation of interleukin 10, 12 and 18 levels in patients with head and neck cancer. J LaryngolOncol. 2007;121:246-52.

Wu YY, Wang JS, Fang Q. [Preliminary evaluation of immunological function in patients with acute lymphocytic leukemia]. Zhongguo Shi Yan Xue Ye XueZaZhi. 2010;18(3):718-20.

Linkov F, Ferris RL, Yurkovetsky Z, et al. Multiplex analysis of cytokines as biomarkers that differentiate benign and malignant thyroid diseases. Proteomics Clin Appl. 2008;2:1575-85.

Kasprzak A, Przewoźna M, Surdyk-Zasada J, et al. The expression of selected neuroendocrine markers and of anti-neoplastic cytokines (IL-2 and IL-12) in lung cancers. Folia Morphol. 2003;62:497-9.

Ye ZB, Ma T, Li H, et al. Expression and significance of intratumoral interleukin-12 and interleukin-18 in human gastric carcinoma. World J Gastroenterol. 2007;13:1747-51.

Paleri V, Pulimood A, Davies G, et al. Interleukins 7 and 12 are expressed in head and neck squamous cancer. ClinOtolaryngol Allied Sci. 2001;26:302-6.

Green VL, Irune E, Prasai A, et al. Serum IL10, IL12 and circulating CD4+ CD25high T regulatory cells in relation to long-term clinical outcome in head and neck squamous cell carcinoma patients. Int J Oncol. 2012; 40:833-9.

Stanilov N, Miteva L, Jovchev J, et al. The prognostic value of preoperative serum levels of IL‐12p40 and IL‐23 for survival of patients with colorectal cancer. APMIS. 2014;122:1223-9.

Mir MA, Maurer MJ, Ziesmer SC, et al. Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma. Blood. 2015;125:992-8.

Wang J, Zhang C, Liu J, et al. Effects of interleukin-12 transfection on proliferation of ovarian cancer SKOV3 cells in vitro and in vivo. Ai Zheng. 2007;26:1292-8.




DOI: http://dx.doi.org/10.14319/ijcto.61.7

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