The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies


In spite of considerable evidence on the regulation of immunity by thyroid hormones, the impact of the thyroid status in tumor immunity is poorly understood. Here, we evaluated the antitumor immune responses evoked in mice with different thyroid status (euthyroid, hyperthyroid, and hypothyroid) that developed solid tumors or metastases after inoculation of syngeneic T lymphoma cells. Hyperthyroid mice showed increased tumor growth along with increased expression of cell cycle regulators compared to hypothyroid and control tumor-bearing mice. However, hypothyroid mice showed a higher frequency of metastases than the other groups. Hyperthyroid mice bearing tumors displayed a lower number of tumor-infiltrating T lymphocytes, lower percentage of functional IFN-γ-producing CD8+ T cells, and higher percentage of CD19+ B cells than euthyroid tumor-bearing mice. However, no differences were found in the distribution of lymphocyte subpopulations in tumor-draining lymph nodes (TDLNs) or spleens among different experimental groups. Interestingly, hypothyroid TDLN showed an increased percentage of regulatory T (Treg) cells, while hyperthyroid mice displayed increased number and activity of splenic NK cells, which frequency declined in spleens from hypothyroid mice. Moreover, a decreased number of splenic myeloid-derived suppressor cells (MDSCs) were found in tumor-bearing hyperthyroid mice as compared to hypothyroid or euthyroid mice. Additionally, hyperthyroid mice showed increased cytotoxic activity, which declined in hypothyroid mice. Thus, low levels of intratumoral cytotoxic activity would favor tumor local growth in hyperthyroid mice, while regional and systemic antitumor response may contribute to tumor dissemination in hypothyroid animals. Our results highlight the importance of monitoring the thyroid status in patients with T cell lymphomas.

Key messages

  • T cell lymphoma phenotype is paradoxically influenced by thyroid status.

  • Hyperthyroidism favors tumor growth and hypothyroidism rises tumor dissemination.

  • Thyroid status affects the distribution of immune cell types in the tumor milieu.

  • Thyroid status also modifies the nature of local and systemic immune responses.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Pinto M, Soares P, Ribatti D (2011) Thyroid hormone as a regulator of tumor induced angiogenesis. Cancer Lett 301(2):119–126

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Barreiro Arcos ML, Sterle HA, Paulazo MA, Valli E, Klecha AJ, Isse B, Pellizas CG, Farias RN, Cremaschi GA (2011) Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression. J Cell Physiol 226(12):3208–3218

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Barreiro Arcos ML, Sterle HA, Vercelli C, Valli E, Cayrol MF, Klecha AJ, Paulazo MA, Diaz Flaque MC, Franchi AM, Cremaschi GA (2013) Induction of apoptosis in T lymphoma cells by long-term treatment with thyroxine involves PKCzeta nitration by nitric oxide synthase. Apoptosis 18(11):1376–1390

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tsui KH, Hsieh WC, Lin MH, Chang PL, Juang HH (2008) Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2. Prostate 68(6):610–619

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Cohen K, Ellis M, Khoury S, Davis PJ, Hercbergs A, Ashur-Fabian O (2011) Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via alphavbeta3 integrin. Mol Cancer Res 9(10):1385–1394

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE, Morgan M, Schlesselman JJ (2000) Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 11(2):111–117

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ko AH, Wang F, Holly EA (2007) Pancreatic cancer and medical history in a population-based case–control study in the San Francisco Bay Area, California. Cancer Causes Control 18(8):809–819

    Article  PubMed  Google Scholar 

  8. 8.

    Hellevik AI, Asvold BO, Bjoro T, Romundstad PR, Nilsen TI, Vatten LJ (2009) Thyroid function and cancer risk: a prospective population study. Cancer Epidemiol Biomarkers Prev 18(2):570–574

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, Hsu L, Krishnamurthy S, Theriault RL, Hortobagyi GN (2005) Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 103(6):1122–1128

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Reddy A, Dash C, Leerapun A, Mettler TA, Stadheim LM, Lazaridis KN, Roberts RO, Roberts LR (2007) Hypothyroidism: a possible risk factor for liver cancer in patients with no known underlying cause of liver disease. Clin Gastroenterol Hepatol 5(1):118–123

    Article  PubMed  Google Scholar 

  11. 11.

    Hassan MM, Kaseb A, Li D, Patt YZ, Vauthey JN, Thomas MB, Curley SA, Spitz MR, Sherman SI, Abdalla EK et al (2009) Association between hypothyroidism and hepatocellular carcinoma: a case–control study in the United States. Hepatology 49(5):1563–1570

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Rennert G, Rennert HS, Pinchev M, Gruber SB (2010) A case–control study of levothyroxine and the risk of colorectal cancer. J Natl Cancer Inst 102(8):568–572

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hercbergs AH, Ashur-Fabian O, Garfield D (2010) Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 17:432–436

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Angelousi AG, Anagnostou VK, Stamatakos MK, Georgiopoulos GA, Kontzoglou KC (2012) Mechanisms in endocrinology: primary HT and risk for breast cancer: a systematic review and meta-analysis. Eur J Endocrinol 17(5):432–436

    Google Scholar 

  15. 15.

    Moeller LC, Fuhrer D (2013) Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer 20(2):R19–R29

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Theodossiou C, Schwarzenberger P (2000) Propylthiouracil reduces xenograft tumor growth in an athymic nude mouse prostate cancer model. Am J Med Sci 319(2):96–99

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Martinez-Iglesias O, Garcia-Silva S, Regadera J, Aranda A (2009) Hypothyroidism enhances tumor invasiveness and metastasis development. PLoS ONE 4(7):e6428

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Sterle HA, Valli E, Cayrol F, Paulazo MA, Martinel Lamas DJ, Diaz Flaque MC, Klecha AJ, Colombo L, Medina VA, Cremaschi GA et al (2014) Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis. J Endocrinol 222(2):243–255

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Cayrol F, Diaz Flaque MC, Fernando T, Yang SN, Sterle HA, Bolontrade M, Amoros M, Isse B, Farias RN, Ahn H et al (2015) Integrin alphavbeta3 acting as membrane receptor for thyroid hormones mediates angiogenesis in malignant T cells. Blood 125(5):841–851

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Barreiro Arcos ML, Gorelik G, Klecha A, Genaro AM, Cremaschi GA (2006) Thyroid hormones increase inducible nitric oxide synthase gene expression downstream from PKC-zeta in murine tumor T lymphocytes. Am J Physiol Cell Physiol 291(2):C327–C336

    Article  PubMed  Google Scholar 

  21. 21.

    Klecha AJ, Genaro AM, Gorelik G, Barreiro Arcos ML, Silberman DM, Schuman M, Garcia SI, Pirola C, Cremaschi GA (2006) Integrative study of hypothalamus-pituitary-thyroid-immune system interaction: thyroid hormone-mediated modulation of lymphocyte activity through the protein kinase C signaling pathway. J Endocrinol 189(1):45–55

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Gutkin DW, Shurin MR (2014) Clinical evaluation of systemic and local immune responses in cancer: time for integration. Cancer Immunol Immunother 63(1):45–57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells 25:267–96. doi: 10.1146/annurev.immunol.25.022106.141609

  25. 25.

    Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Croci DO, Zacarias Fluck MF, Rico MJ, Matar P, Rabinovich GA, Scharovsky OG (2007) Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol Immunother 56(11):1687–1700

    Article  PubMed  Google Scholar 

  27. 27.

    Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA (2004) Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: a potential mechanism of tumor-immune privilege. Cancer Cell 5(3):241–251

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Blidner AG, Salatino M, Mascanfroni ID, Diament MJ, Bal de Kier Joffe E, Jasnis MA, Klein SM, Rabinovich GA (2015) Differential response of myeloid-derived suppressor cells to the nonsteroidal anti-inflammatory agent indomethacin in tumor-associated and tumor-free microenvironments. J Immunol 194(7):3452–3462

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Reiche EM, Nunes SO, Morimoto HK (2004) Stress, depression, the immune system, and cancer. Lancet Oncol 5(10):617–625

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Hammacher A, Thompson EW, Williams ED (2005) Interleukin-6 is a potent inducer of S100P, which is up-regulated in androgen-refractory and metastatic prostate cancer. Int J Biochem Cell Biol 37(2):442–450

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Smith HA, Kang Y (2013) The metastasis-promoting roles of tumor-associated immune cells. J Mol Med 91(4):411–429

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Shu ST, Martin CK, Thudi NK, Dirksen WP, Rosol TJ (2010) Osteolytic bone resorption in adult T-cell leukemia/lymphoma. Leuk Lymphoma 51(4):702–714

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Maffuz A, Barroso-Bravo S, Najera I, Zarco G, Alvarado-Cabrero I, Rodriguez-Cuevas SA (2006) Tumor size as predictor of microinvasion, invasion, and axillary metastasis in ductal carcinoma in situ. J Exp Clin Cancer Res 25(2):223–227

    CAS  PubMed  Google Scholar 

  34. 34.

    Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, Kreike B, Zhang Y, Wang Y, Ishwaran H et al (2007) Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A 104(16):6740–6745

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Mihara S, Suzuki N, Wakisaka S, Suzuki S, Sekita N, Yamamoto S, Saito N, Hoshino T, Sakane T (1999) Effects of thyroid hormones on apoptotic cell death of human lymphocytes. J Clin Endocrinol Metab 84(4):1378–1385

    CAS  PubMed  Google Scholar 

  36. 36.

    Rosenquist R, Davi F, Stamatopoulos K (2013) Antigens in lymphoma development—current knowledge and future directions. Semin Cancer Biol 23(6):397–398

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM et al (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21):2159–2169

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, Montserrat E, Campo E, Banham AH (2006) High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 108(9):2957–2964

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    De Vito P, Incerpi S, Pedersen JZ, Luly P, Davis FB, Davis PJ (2011) Thyroid hormones as modulators of immune activities at the cellular level. Thyroid 21(8):879–890

    Article  PubMed  Google Scholar 

  40. 40.

    Alamino VA, Mascanfroni ID, Montesinos MM, Gigena N, Donadio AC, Blidner AG, Milotich SI, Cheng SY, Masini-Repiso AM, Rabinovich GA et al (2015) Antitumor responses stimulated by dendritic cells are improved by triiodothyronine binding to the thyroid hormone receptor beta. Cancer Res 75(7):1265–1274

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Namm JP, Li Q, Lao X, Lubman DM, He J, Liu Y, Zhu J, Wei S, Chang AE (2012) B lymphocytes as effector cells in the immunotherapy of cancer. J Surg Oncol 105(4):431–435

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M (2013) CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am J Hematol 88(4):273–276

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, Chen W, Kutok JL, Rabinovich GA, Shipp MA (2007) The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 104(32):13134–13139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Gassmann P, Haier J (2008) The tumor cell-host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis 25(2):171–181

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Bonzheim I, Geissinger E, Tinguely M, Roth S, Grieb T, Reimer P, Wilhelm M, Rosenwald A, Muller-Hermelink HK, Rudiger T (2008) Evaluation of FoxP3 expression in peripheral T-cell lymphoma. Am J Clin Pathol 130(4):613–619

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Marzano AV, Vezzoli P, Fanoni D, Venegoni L, Berti E (2009) Primary cutaneous T-cell lymphoma expressing FOXP3: a case report supporting the existence of malignancies of regulatory T cells. J Am Acad Dermatol 61(2):348–355

    Article  PubMed  Google Scholar 

  47. 47.

    Yano H, Ishida T, Inagaki A, Ishii T, Kusumoto S, Komatsu H, Iida S, Utsunomiya A, Ueda R (2007) Regulatory T-cell function of adult T-cell leukemia/lymphoma cells. Int J Cancer 120(9):2052–2057

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Tadmor T, Fell R, Polliack A, Attias D (2013) Absolute monocytosis at diagnosis correlates with survival in diffuse large B-cell lymphoma-possible link with monocytic myeloid-derived suppressor cells. Hematol Oncol 31(2):65–71

    Article  PubMed  Google Scholar 

  49. 49.

    Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M (2009) Modulators of arginine metabolism support cancer immunosurveillance. BMC Immunol 10:1

    Article  PubMed  PubMed Central  Google Scholar 

Download references


This work was supported by the University of Buenos Aires (UBACYT 20020130100289BA) to G.A.C., the National Agency for Science and Technology (ANPCYT, PICT 2012–1328 to G.A.C. and PICT 2012–2440 to G.A.R.), and Fundación to G.A.R. We also thank Fundación Barón for kind support.

Author information



Corresponding author

Correspondence to G. A. Cremaschi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.


(PDF 1388 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sterle, H.A., Barreiro Arcos, M.L., Valli, E. et al. The thyroid status reprograms T cell lymphoma growth and modulates immune cell frequencies. J Mol Med 94, 417–429 (2016).

Download citation


  • T cell lymphoma
  • Thyroid hormones
  • Proliferation
  • Apoptosis
  • Antitumor immune response