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Regulatory T cells and plasmacytoid dendritic cells contribute to the immune escape of papillary thyroid cancer coexisting with multinodular non-toxic goiter

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Abstract

Immunosuppressive lymphocytes, such as regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs), play crucial roles in tumor escape. To investigate the roles of Tregs and pDCs in papillary thyroid cancer (PTC) plus multinodular non-toxic goiter (MNG), thyroid tissue and blood samples from 30 patients with PTC plus MNG and 30 MNG alone were analyzed for CD4+ T cell, CD8+ T cell, FoxP3+ Treg, ICOS+FoxP3+ Treg, and pDC numbers by immunohistochemistry (IHC), immunofluorescence, and flow cytometry. Plasma concentration of the cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β) were measured by enzyme-linked immunosorbent assay as well. Both in thyroid tissue and peripheral blood, the numbers of Foxp3+ Treg were significantly higher in patients with PTC plus MNG compared to patients with MNG alone; and as a prognostic marker, ICOS+Foxp3+ Tregs represent a stronger predictor of disease progression than the total numbers of Foxp3+ Tregs. Furthermore, a positive correlation between pDC and ICOS+Foxp3+ Treg numbers in tissue of patients with PTC plus MNG was observed, suggesting that PTC-derived pDCs may induce the differentiation of naive CD4+ T cells into ICOS+Foxp3+Tregs. This may be one of the mechanisms underlying tumor escape in PTC plus MNG patients. Our results suggest that Tregs and pDCs together contribute to the tumor escape in patients with PTC plus MNG.

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References

  1. O. Dohan, Z. Baloch, Z. Banrevi, V. Livolsi, N. Carrasco, Rapid communication: predominant intracellular overexpression of the Na+/I− symporter (NIS) in a large sampling of thyroid cancer cases. J. Clin. Endocrinol. Metab. 86, 2697–2700 (2001)

    Article  PubMed  CAS  Google Scholar 

  2. F. Pacini, Changing natural history of differentiated thyroid cancer. Endocrine 42(2), 229–230 (2012)

    Article  PubMed  CAS  Google Scholar 

  3. L. Wartofsky, Increasing world incidence of thyroid cancer: increased detection or higher radiation exposure. Hormones (Athens) 9(2), 103–108 (2010)

    Google Scholar 

  4. L. Davies, H.G. Welch, Increasing incidence of thyroid cancer in the United States. 1973–2002. JAMA 295, 2164–2167 (2006)

    Article  PubMed  CAS  Google Scholar 

  5. L. Pagano, M. Caputo, M.T. Samà, V. Garbaccio, M. Zavattaro, M.G. Mauri, F. Prodam, P. Marzullo, R. Boldorini, G. Valente, G. Aimaretti, Clinical-pathological changes in differentiated thyroid cancer (DTC) over time (1997–2010): data from the University Hospital “Maggiore della Carità” in Novara. Endocrine 42, 382–390 (2012)

    Article  PubMed  CAS  Google Scholar 

  6. B.A. Kilfoy, T. Zheng, T.R. Holford et al., International patterns and trends in thyroid cancer incidence, 1973–2002. Cancer Causes Control 20(5), 525–531 (2009)

    Article  PubMed  Google Scholar 

  7. D.S. McLeod, D.S. Cooper, The incidence and prevalence of thyroid autoimmunity. Endocrine 42(2), 252–265 (2012)

    Article  PubMed  CAS  Google Scholar 

  8. M.R. Pelizzo, P. Bernante, A. Toniato, A. Fassina, Frequency of thyroid carcinoma in a recent series of 539 consecutive thyroidectomies for multinodular goiter. Tumori 83, 653–655 (1997)

    PubMed  CAS  Google Scholar 

  9. I. Sachmechi, E. Miller, R. Varatharajah, A. Chernys, Z. Carroll, E. Kissin, Thyroid carcinoma in single cold nodules and in cold nodules of multinodular goiters. Endocr. Pract. 6, 5–7 (2000)

    Article  PubMed  CAS  Google Scholar 

  10. J. Modi, A. Patel, R. Terrell, R.M. Tuttle, G.L. Francis, Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes. J. Clin. Endocrinol. Metab. 88, 4418–4425 (2003)

    Article  PubMed  CAS  Google Scholar 

  11. S. Gupta, A. Patel, A. Folstad, C. Fenton, C.A. Dinauer, R.M. Tuttle, R. Conran, G.L. Francis, Infiltration of differentiated thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival for children and young adults. J. Clin. Endocrinol. Metab. 86, 1346–1354 (2001)

    Article  PubMed  CAS  Google Scholar 

  12. S. Matsubayashi, K. Kawai, Y. Matsumoto, T. Mukuta, T. Morita, K. Hirai, F. Matsuzuka, K. Kakudoh, K. Kuma, H. Tamai, The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland. J. Clin. Endocrinol. Metab. 80, 3421–3424 (1995)

    Article  PubMed  CAS  Google Scholar 

  13. J.D. French, Z.J. Weber, D.L. Fretwell, S. Said, J.P. Klopper, B.R. Haugen, Tumor-associated lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary thyroid cancer. J. Clin. Endocrinol. Metab. 95(5), 2325–2333 (2010)

    Article  PubMed  CAS  Google Scholar 

  14. F. Gogali, G. Paterakis, G.Z. Rassidakis, G. Kaltsas, C.I. Liakou, P. Gousis, E. Neonakis, M.N. Manoussakis, C. Liapi, Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NK cells in the papillary carcinoma of thyroid. J. Clin. Endocrinol. Metab. 97(5), 1474–1482 (2012)

    Article  PubMed  CAS  Google Scholar 

  15. G.J. Bates, S.B. Fox, C. Han, R.D. Leek, J.F. Garcia, A.L. Harris, A.H. Banham, Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373–5380 (2006)

    Article  PubMed  Google Scholar 

  16. J. Fu, D. Xu, Z. Liu, M. Shi, P. Zhao, B. Fu, Z. Zhang, H. Yang, H. Zhang, C. Zhou, J. Yao, L. Jin, H. Wang, Y. Yang, Y.X. Fu, F.S. Wang, Increased regulatory T cells correlate with CD8+ T cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132, 2328–2339 (2007)

    Article  PubMed  Google Scholar 

  17. N. Hiraoka, K. Onozato, T. Kosuge, S. Hirohashi, Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin. Cancer Res. 12, 5423–5434 (2006)

    Article  PubMed  CAS  Google Scholar 

  18. X.L. Yuan, L. Chen, M.X. Li, P. Dong, J. Xue, J. Wang, T.T. Zhang, X.A. Wang, F.M. Zhang, H.L. Ge, L.S. Shen, D. Xu, Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner. Clin. Immunol. 134, 277–288 (2010)

    Article  PubMed  CAS  Google Scholar 

  19. T. Ito, S. Hanabuchi, Y.H. Wang, W.R. Park, K. Arima, L. Bover, F.X. Qin, M. Gilliet, Y.J. Liu, Two functional subsets of Foxp3+ regulatory T cells in human thymus and periphery. Immunity 28, 870–880 (2008)

    Article  PubMed  CAS  Google Scholar 

  20. K. McKenna, A.S. Beignon, N. Bhardwaj, Plasmacytoid dendritic cells: linking innate and adaptive immunity. J. Virol. 79, 17–27 (2005)

    Article  PubMed  CAS  Google Scholar 

  21. Y.J. Liu, Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259–262 (2001)

    Article  PubMed  CAS  Google Scholar 

  22. J. Tel, A.J. Lambeck, L.J. Cruz, P.J. Tacken, I.J. de Vries, C.G. Figdor, Human plasmacytoid dendritic cells phagocytose, process, and present exogenous particulate antigen. J. Immunol. 184, 4276–4283 (2010)

    Article  PubMed  CAS  Google Scholar 

  23. G. Gerlini, C. Urso, G. Mariotti, P. Di Gennaro, D. Palli, P. Brandani, A. Salvadori, N. Pimpinelli, U.M. Reali, L. Borgognoni, Plasmacytoid dendritic cells represent a major dendritic cell subset in sentinel lymph nodes of melanoma patients and accumulate in metastatic nodes. Clin. Immunol. 125, 184–193 (2007)

    Article  PubMed  CAS  Google Scholar 

  24. E. Hartmann, B. Wollenberg, S. Rothenfusser, M. Wagner, D. Wellisch, B. Mack, T. Giese, O. Gires, S. Endres, G. Hartmann, Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res. 63, 6478–6487 (2003)

    PubMed  CAS  Google Scholar 

  25. I. Treilleux, J.Y. Blay, N. Bendriss-Vermare, I. Ray-Coquard, T. Bachelot, J.P. Guastalla, A. Bremond, S. Goddard, J.J. Pin, C. Barthelemy-Dubois, S. Lebecque, Dendritic cell infiltration and prognosis of early stage breast cancer. Clin. Cancer Res. 10, 7466–7474 (2004)

    Article  PubMed  CAS  Google Scholar 

  26. S.I. Labidi-Galy, V. Sisirak, P. Meeus, M. Gobert, I. Treilleux, A. Bajard, J.D. Combes, J. Faget, F. Mithieux, A. Cassignol, O. Tredan, I. Durand, C. Ménétrier-Caux, C. Caux, J.Y. Blay, I. Ray-Coquard, N. Bendriss-Vermare, Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res. 71(16), 5423–5434 (2011)

    Article  PubMed  CAS  Google Scholar 

  27. T. Ito, M. Yang, Y.H. Wang, R. Lande, J. Gregorio, O.A. Perng, X.F. Qin, Y.J. Liu, M. Gilliet, Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand. J. Exp. Med. 204, 105–115 (2007)

    Article  PubMed  CAS  Google Scholar 

  28. American Joint Committee on Cancer, Thyroid, AJCC Cancer Staging Handbook, 6th edn. (Springer, New York, 2002), pp. 89–98

    Google Scholar 

  29. R. Khattri, T. Cox, S.A. Yasayko, F. Ramsdell, An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003)

    Article  PubMed  CAS  Google Scholar 

  30. J.D. Fontenot, J.P. Rasmussen, L.M. Williams, J.L. Dooley, A.G. Farr, A.Y. Rudensky, Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    Article  PubMed  CAS  Google Scholar 

  31. T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, W. Zou, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004)

    Article  PubMed  CAS  Google Scholar 

  32. C. Conrad, J. Gregorio, Y.H. Wang, T. Ito, S. Meller, S. Hanabuchi, S. Anderson, N. Atkinson, P.T. Ramirez, Y.J. Liu, R. Freedman, M. Gilliet, Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3 + T-regulatory cells. Cancer Res. 72(20), 5240–5249 (2012)

    Article  PubMed  CAS  Google Scholar 

  33. S. Schroder, W. Schwartz, W. Rehpenning, T. Loning, Bocker W Dendritic/Langerhans cells and prognosis in patients with papillary thyroid carcinomas. Am. J. Clin. Pathol. 89, 295–300 (1988)

    PubMed  CAS  Google Scholar 

  34. A. Batistatou, V. Zolota, C.D. Scopa, S-100 protein+ dendritic cells and CD34+ dendritic interstitial cells in thyroid lesions. Endocr Pathol 13(2), 111–115 (2002)

    Article  PubMed  CAS  Google Scholar 

  35. E. Gehrie, W. Van der Touw, J.S. Bromberg, J.C. Ochando, Plasmacytoid dendritic cells in tolerance. Methods Mol. Biol. 677, 127–147 (2011)

    Article  PubMed  Google Scholar 

  36. I. Treilleux, J.Y. Blay, N. Bendriss-Vermare, I. Ray-Coquard, T. Bachelot, J.P. Guastalla, A. Bremond, S. Goddard, J.J. Pin, C. Barthelemy-Dubois, S. Lebecque, Dendritic cell infiltration and prognosis of early stage breast cancer. Clin. Cancer Res. 10, 7466–7474 (2004)

    Article  PubMed  CAS  Google Scholar 

  37. W. Vermi, R. Bonecchi, F. Facchetti, D. Bianchi, S. Sozzani, S. Festa, A. Berenzi, M. Cella, M. Colonna, Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas. J. Pathol. 200, 255–268 (2003)

    Article  PubMed  Google Scholar 

  38. M.V. Dhodapkar, R.M. Steinman, J. Krasovsky, C. Munz, N. Bhardwaj, Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001)

    Article  PubMed  CAS  Google Scholar 

  39. M.K. Levings, S. Gregori, E. Tresoldi, S. Cazzaniga, C. Bonini, M.G. Roncarolo, Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4 + Tr cells. Blood 105, 1162–1169 (2005)

    Article  PubMed  CAS  Google Scholar 

  40. D.H. Munn, A.L. Mellor, Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007)

    Article  PubMed  CAS  Google Scholar 

  41. W. Chen, X. Liang, A.J. Peterson, D.H. Munn, B.R. Blazar, The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol. 181(8), 5396–5404 (2008)

    PubMed  CAS  Google Scholar 

  42. M.D. Sharma, B. Baban, P. Chandler, D.Y. Hou, N. Singh, H. Yagita, M. Azuma, B.R. Blazar, A.L. Mellor, D.H. Munn, Plasmacytoid dendritic cells from mouse tumor draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570–2582 (2007)

    Article  PubMed  CAS  Google Scholar 

  43. A. Stift, M. Sachet, R. Yagubian, C. Bittermann, P. Dubsky, C. Brostjan, R. Pfragner, B. Niederle, R. Jakesz, M. Gnant, J. Friedl, Dendritic cell vaccination in medullary thyroid carcinoma. Clin. Cancer Res. 10, 2944–2953 (2004)

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Haiyang Xie, Xiaowen Feng, Xiaoqing Tang, Jing Ying, and Rong Su in the Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, School of Medicine, Zhejiang University for technical support in IHC and Flow cytometry. Hang Yu and Xiaomei Huang were supported by the grant of The National Natural Science Foundation of China (81071964/H1617); Xiaosun Liu was supported by the grants of The Scientific Research Foundation for The Returned Overseas (491010-G51102) and The Qianjiang Talent Program of Zhejiang Province (2012R10046).

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The experiments comply with the current laws of the country in which they were performed.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Gastrointestinal and Thyroid Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79, Qingchun Road, Hangzhou, 310003, Zhejiang, China

    Hang Yu, Xiaomei Huang, Xiaosun Liu, Hailong Jin, Ge’er Zhang, Qing Zhang & Jiren Yu

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  1. Hang Yu
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Correspondence to Jiren Yu.

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Hang Yu and Xiaomei Huang contributed equally to this work.

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Yu, H., Huang, X., Liu, X. et al. Regulatory T cells and plasmacytoid dendritic cells contribute to the immune escape of papillary thyroid cancer coexisting with multinodular non-toxic goiter. Endocrine 44, 172–181 (2013). https://doi.org/10.1007/s12020-012-9853-2

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