Advertisement

Tumor Biology

, Volume 34, Issue 4, pp 2031–2039 | Cite as

Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions

  • Farhad Jadidi-Niaragh
  • Ghasem Ghalamfarsa
  • Mehdi Yousefi
  • Mina Hajifaraj Tabrizi
  • Fazel Shokri
Review

Abstract

Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4+ Tregs in CLL patients. However, the precise role of these cells in the immunopathology of CLL is not well known. While targeting Tregs in cancer diseases seems to be an interesting immunotherapeutic approach, such therapeutic interventions in CLL might be deleterious due to suppression of the tumor-specific adaptive and innate immune responses. Thus, the precise biological and regulatory functions of all Tregs subsets should be carefully investigated before planning any immunotherapeutic interventions based on targeting of Tregs. In this communication, we review the recent data published on immunobiology of Tregs in CLL and discuss about the possibility of targeting Tregs in CLL.

Keywords

Chronic lymphocytic leukemia Regulatory T cells Leukemic B cells Disease progression Hematopoietic malignancies 

Notes

Conflicts of interest

None

References

  1. 1.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.CrossRefPubMedGoogle Scholar
  2. 2.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352:804–15.CrossRefPubMedGoogle Scholar
  3. 3.
    Kay NE, Shanafelt TD. Prognostic factors in chronic lymphocytic leukemia. Current Hematologic Malignancy Reports. 2007;2:49–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Hojjat-Farsangi M, Jeddi-Tehrani M, Razavi SM, Sharifian RA, Mellstedt H, Shokri F, et al. Immunoglobulin heavy chain variable region gene usage and mutational status of the leukemic B cells in Iranian patients with chronic lymphocytic leukemia. Cancer Science. 2009;100:2346–53.CrossRefPubMedGoogle Scholar
  5. 5.
    Mellstedt H, Choudhury A. T and B cells in B-chronic lymphocytic leukaemia: Faust, mephistopheles and the pact with the devil. Cancer Immunology, Immunotherapy. 2006;55:210–20.CrossRefPubMedGoogle Scholar
  6. 6.
    Zaknoen S, Kay N. Immunoregulatory cell dysfunction in chronic B-cell leukemias. Blood reviews. 1990;4:165–74.CrossRefPubMedGoogle Scholar
  7. 7.
    Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–25.CrossRefPubMedGoogle Scholar
  8. 8.
    Giannopoulos K, Schmitt M, Kowal M, Wlasiuk P, Bojarska-Junak A, Chen J, et al. Characterization of regulatory T cells in patients with B-cell chronic lymphocytic leukemia. Oncology reports. 2008;20:677–82.PubMedGoogle Scholar
  9. 9.
    Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18:723–37.PubMedGoogle Scholar
  10. 10.
    Jadidi-Niaragh F, Mirshafiey A. Regulatory T-cell as orchestra leader in immunosuppression process of multiple sclerosis. Immunopharmacol Immunotoxicol. 2011;33:545–67.CrossRefPubMedGoogle Scholar
  11. 11.
    Mills KHG. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol. 2004;4:841–55.CrossRefPubMedGoogle Scholar
  12. 12.
    Jadidi-Niaragh F, Mirshafiey A. The deviated balance between regulatory T cell and Th17 in autoimmunity. Immunopharmacol Immunotoxicol. 2012;34:727–39.CrossRefPubMedGoogle Scholar
  13. 13.
    Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, et al. Thymic selection of CD4+ CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2:301–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, et al. Crucial role of FOXP3 in the development and function of human CD25+ CD4+ regulatory T cells. Int Immunol. 2004;16:1643–56.CrossRefPubMedGoogle Scholar
  15. 15.
    Morgan ME, van Bilsen JHM, Bakker AM, Heemskerk B, Schilham MW, Hartgers FC, et al. Expression of FOXP3 mRNA is not confined to CD4+ CD25+ T regulatory cells in humans. Hum Immunol. 2005;66:13–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, et al. FOXP3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445:771–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Passerini L, Allan SE, Battaglia M, Di Nunzio S, Alstad AN, Levings MK, et al. Stat5-signaling cytokines regulate the expression of FOXP3 in CD4+ CD25+ regulatory T cells and CD4+ CD25− effector T cells. Int Immunol. 2008;20:421–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Roncarolo MG, Gregori S. Is FOXP3 a bona fide marker for human regulatory T cells. Eur J Immunol. 2008;38:925–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the FOXP3 gene in regulatory T-cell fate. Nature. 2010;463:808–12.CrossRefPubMedGoogle Scholar
  20. 20.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor FOXP3. Science. 2003;299:1057–61.CrossRefPubMedGoogle Scholar
  21. 21.
    Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. The Journal of experimental medicine. 2006;203:1701–11.CrossRefPubMedGoogle Scholar
  23. 23.
    Lila N, Rouas-Freiss N, Dausset J, Carpentier A, Carosella ED. Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism. Proc Natl Acad Sci. 2001;98:12150–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Grazia Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10 secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50.CrossRefGoogle Scholar
  25. 25.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79.CrossRefPubMedGoogle Scholar
  26. 26.
    Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal RM, Roncarolo MG. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol. 2001;166:5530–9.PubMedGoogle Scholar
  27. 27.
    Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes and infection. 2001;3:947–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Weiner HL. Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–14.CrossRefPubMedGoogle Scholar
  29. 29.
    Smith TRF, Kumar V. Revival of CD8+ Treg-mediated suppression. Trends in immunology. 2008;29:337–42.CrossRefPubMedGoogle Scholar
  30. 30.
    Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500.CrossRefPubMedGoogle Scholar
  31. 31.
    Niederkorn JY. Emerging concepts in CD8+ T regulatory cells. Curr Opin Immunol. 2008;20:327–31.CrossRefPubMedGoogle Scholar
  32. 32.
    Joosten SA, Ottenhoff THM. Human CD4 and CD8 regulatory T cells in infectious diseases and vaccination. Hum Immunol. 2008;69:760–70.CrossRefPubMedGoogle Scholar
  33. 33.
    Cortesini R, LeMaoult J, Ciubotariu R, Cortesini NSF. CD8+ CD28− T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity. Immunol Rev. 2001;182:201–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Mahic M, Henjum K, Yaqub S, Bjørnbeth BA, Torgersen KM, Taskén K, et al. Generation of highly suppressive adaptive CD8+ CD25+ FOXP3+ regulatory T cells by continuous antigen stimulation. Eur J Immunol. 2008;38:640–6.CrossRefPubMedGoogle Scholar
  35. 35.
    So T, Lee SW, Croft M. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine & growth factor reviews. 2008;19:253–62.CrossRefGoogle Scholar
  36. 36.
    Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Beyer M, Schultze JL. Regulatory T cells in cancer. Blood. 2006;108:804–11.CrossRefPubMedGoogle Scholar
  38. 38.
    Wang HY, Wang RF. Regulatory T cells and cancer. Curr Opin Immunol. 2007;19:217–23.CrossRefPubMedGoogle Scholar
  39. 39.
    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.PubMedGoogle Scholar
  40. 40.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, 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.PubMedGoogle Scholar
  41. 41.
    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. Nature medicine. 2004;10:942–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N, et al. CD4 (+) CD25 high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunology, Immunotherapy. 2006;55:1064–71.CrossRefPubMedGoogle Scholar
  43. 43.
    Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 2005;65:2457–64.CrossRefPubMedGoogle Scholar
  44. 44.
    Viguier M, Lemaître F, Verola O, Cho MS, Gorochov G, Dubertret L, et al. FOXP3 expressing CD4+ CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173:1444–53.PubMedGoogle Scholar
  45. 45.
    Wang J, Ke XY. The four types of Tregs in malignant lymphomas. Journal of Hematology & Oncology. 2011;4:50.CrossRefGoogle Scholar
  46. 46.
    Kelley TW, Parker CJ. CD4 (+)CD25 (+)FOXP3 (+) regulatory T cells and hematologic malignancies. Frontiers in bioscience (Scholar edition). 2010;2:980–92.CrossRefGoogle Scholar
  47. 47.
    Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE. CD4+ T-cell immune response to large B-cell non-Hodgkin’s lymphoma predicts patient outcome. J Clin Oncol. 2001;19:720–6.PubMedGoogle Scholar
  48. 48.
    Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93:193–200.CrossRefPubMedGoogle Scholar
  49. 49.
    Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006;108:2957–64.CrossRefPubMedGoogle Scholar
  50. 50.
    de Rezende LCD, Silva IV, Rangel LBA, Guimarães MCC. Regulatory T cell as a target for cancer therapy. Arch Immunol Ther Exp. 2010;58:179–90.CrossRefGoogle Scholar
  51. 51.
    Feng LL, Wang X. Targeting FOXP3+ regulatory T cells-related immunosuppression for cancer immunotherapy. Chin Med J. 2010;123:3334–42.PubMedGoogle Scholar
  52. 52.
    Weiss L, Melchardt T, Egle A, Grabmer C, Greil R, Tinhofer I. Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia. Cancer. 2011;117:2163–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Giannopoulos KM, Schmitt PW. The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide. Leukemia. 2007;22:222–4.PubMedGoogle Scholar
  54. 54.
    D'Arena G, D'Auria F, Simeon V, Laurenti L, Deaglio S, Mansueto G, et al. A shorter time to the first treatment may be predicted by the absolute number of regulatory T-cells in patients with Rai stage 0 chronic lymphocytic leukemia. Am J Hematol. 2012;87:628–31.CrossRefPubMedGoogle Scholar
  55. 55.
    Jak M, Mous R, Remmerswaal EBM, Spijker R, Jaspers A, Yagüe A, et al. Enhanced formation and survival of CD4+ CD25hi FOXP3+ T-cells in chronic lymphocytic leukemia. Leukemia & lymphoma. 2009;50:788–801.CrossRefGoogle Scholar
  56. 56.
    D'Arena G, Laurenti L, Minervini MM, Deaglio S, Bonello L, De Martino L, et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res. 2011;35:363–8.CrossRefPubMedGoogle Scholar
  57. 57.
    Piper KP, Karanth M, McLarnon A, Kalk E, Khan N, Murray J, et al. Chronic lymphocytic leukaemia cells drive the global CD4+ T cell repertoire towards a regulatory phenotype and leads to the accumulation of CD4+ forkhead box P3+ T cells. Clin Exp Immunol. 2011;166:154–63.CrossRefPubMedGoogle Scholar
  58. 58.
    Perry C, Herishanu Y, Hazan-Halevy I, Kay S, Bdolach N, Naparstek E, et al. Reciprocal changes in regulatory T cells and Th17 helper cells induced by exercise in patients with chronic lymphocytic leukemia. Leukemia and Lymphoma. 2012;53:1807–10.CrossRefPubMedGoogle Scholar
  59. 59.
    Jadidi-Niaragh F, Yousefi M, Memarian A, Hojjat-Farsangi M, Khoshnoodi J, Razavi SM, et al. Increased frequency of CD8(+) and CD4(+) regulatory T cells in chronic lymphocytic leukemia: association with disease progression. Cancer Investigation. 2013;31:121–31.CrossRefPubMedGoogle Scholar
  60. 60.
    Biancotto A, Dagur PK, Fuchs JC, Wiestner A, Bagwell CB, McCoy Jr JP. Phenotypic complexity of T regulatory subsets in patients with B-chronic lymphocytic leukemia. Mod Pathol. 2012;25:246–59.PubMedGoogle Scholar
  61. 61.
    Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C. Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression (vol 18, pg 678, 2012). Clin Cancer Res. 2012;18:3714–4.Google Scholar
  62. 62.
    Prabhala RH, Neri P, Bae JE, Tassone P, Shammas MA, Allam CK, et al. Dysfunctional T regulatory cells in multiple myeloma. Blood. 2006;107:301–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Lindqvist CA, Christiansson LH, Thörn I, Mangsbo S, Paul-Wetterberg G, Sundström C, et al. Both CD4+ FOXP3+ and CD4+ FOXP3− T cells from patients with B-cell malignancy express cytolytic markers and kill autologous leukaemic B cells in vitro. Immunology. 2011;133:296–306.CrossRefPubMedGoogle Scholar
  64. 64.
    Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Strömberg U, Loskog AS. T regulatory cells control T cell proliferation partly by the release of soluble CD25 in patients with B cell malignancies. Immunology. 2010;131:371–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Lindqvist CA, Loskog ASI. T regulatory cells in B-cell malignancy—tumor support or kiss of death. Immunology. 2012;135:255–60.CrossRefPubMedGoogle Scholar
  66. 66.
    Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. Malignant B cells skew the balance of regulatory T cells and Th17 cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 2009;69:5522–30.CrossRefPubMedGoogle Scholar
  67. 67.
    Jadidi-Niaragh F, Ghalamfarsa G, Memarian A, Asgarian-Omran H, Razavi SM, Sarrafnejad A, et al. Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia. Tumor Biology. 2013;34:929–40.CrossRefPubMedGoogle Scholar
  68. 68.
    Perry C, Hazan-Halevy I, Kay S, Cipok M, Grisaru D, Deutsch V, et al. Increased CD39 expression on CD4(+) T lymphocytes has clinical and prognostic significance in chronic lymphocytic leukemia. Ann Hematol. 2012;91:1271–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Han Y, Wu J, Bi L, Xiong S, Gao S, Yin L, et al. Malignant B cells induce the conversion of CD4+ CD25− T cells to regulatory T cells in B-cell non-Hodgkin lymphoma. PLoS One. 2011;6:e28649.CrossRefPubMedGoogle Scholar
  70. 70.
    Gowda A, Ramanunni A, Cheney C, Rozewski D, Kindsvogel W, Lehman A, et al. Differential effects of IL-2 and IL-21 on expansion of the CD4(+)CD25(+)FOXP3(+) T regulatory cells with redundant roles in natural killer cell mediated antibody dependent cellular cytotoxicity in chronic lymphocytic leukemia. Mabs. 2010;2:35–41.CrossRefPubMedGoogle Scholar
  71. 71.
    Jadidi-Niaragh F, Jeddi-Tehrani M, Ansaripour B, Razavi SM, Sharifian RA, Shokri F. Reduced frequency of NKT-like cells in patients with progressive chronic lymphocytic leukemia. Medical Oncology. 2012;29:3561–9.CrossRefPubMedGoogle Scholar
  72. 72.
    Christopoulos P, Pfeifer D, Bartholomé K, Follo M, Timmer J, Fisch P, et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood. 2011;117:3836–46.CrossRefPubMedGoogle Scholar
  73. 73.
    Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunology, Immunotherapy. 2006;55:197–209.CrossRefPubMedGoogle Scholar
  74. 74.
    Palma M, Hansson L, Choudhury A, Näsman-Glaser B, Eriksson I, Adamson L, et al. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunology, Immunotherapy. 2012;61:865–79.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Farhad Jadidi-Niaragh
    • 1
  • Ghasem Ghalamfarsa
    • 2
  • Mehdi Yousefi
    • 3
  • Mina Hajifaraj Tabrizi
    • 4
  • Fazel Shokri
    • 1
    • 5
  1. 1.Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
  2. 2.Cellular and Molecular Research CenterYasuj University of Medical SciencesYasujIran
  3. 3.Department of Immunology, Faculty of MedicineTabriz University of Medical SciencesTabrizIran
  4. 4.Department of Medical GeneticsTehran University of Medical SciencesTehranIran
  5. 5.Monoclonal Antibody Research Center, Avicenna Research InstituteAcademic Center for Education, Culture and Research (ACECR)TehranIran

Personalised recommendations