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Microenvironment, Cross-Talk, and Immune Escape Mechanisms

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Hodgkin Lymphoma

Part of the book series: Hematologic Malignancies ((HEMATOLOGIC))

Abstract

A microenvironment can be defined as the environmental conditions of a relatively small, localized area. The tumor cells in Hodgkin lymphoma (HL) most often comprise less than 1% of the cells in the tumor mass, whereas more than 99% of the cells can be considered the microenvironment of these tumor cells. The HL tumor cells probably develop in the context of a deregulated immune response where tumor precursor cells undergo a malignant transformation simultaneously with a tumor-cell-induced adaptation of the composition and reactivity of the inflammatory cells. The tumor cells actively attract specific types of immune cells and they shape the microenvironment to their own benefit. There is an extensive tumor cell promoting and protective cross-talk between the two components. Although the precise function of the microenvironment is not entirely clear, it plays an essential role in the pathogenesis of HL. This chapter describes the current knowledge on the function of the microenvironment, covering both tumor cell promoting signals and immune escape mechanisms.

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References

  1. Poppema S, Delsol G, Pileri SA, et al. Nodular lymphocyte predominant Hodgkin lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.

    Google Scholar 

  2. Stein H, Delsol G, Pileri SA, et al. Classical Hodgkin lymphoma, introduction. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.

    Google Scholar 

  3. Atayar C, van den Berg A, Blokzijl T, et al. Hodgkin lymphoma associated T-cells exhibit a transcription factor profile consistent with distinct lymphoid compartments. J Clin Pathol. 2007;60:1092–7.

    Article  PubMed  Google Scholar 

  4. Carbone A, Gloghini A, Cabras A, et al. Differentiating germinal center-derived lymphomas through their cellular microenvironment. Am J Hematol. 2009;84:435–8.

    Article  PubMed  CAS  Google Scholar 

  5. Oudejans JJ, Jiwa NM, Kummer JA, et al. Analysis of major histocompatibility complex class I expression on Reed-Sterberg cells in relation to the cytotoxic T-cell response in Epstein–Barr virus-positive and -negative Hodgkin’s disease. Blood. 1996;87:3844–51.

    PubMed  CAS  Google Scholar 

  6. Poppema S. Immunology of Hodgkin’s disease. Ballieres Clin Haematol. 1996;9:447–57.

    Article  CAS  Google Scholar 

  7. Wolf M, Albrecht S, Marki C. Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int J Biochem Cell Biol. 2008;40:1185–98.

    Article  PubMed  CAS  Google Scholar 

  8. Von Bonin A, Huhn J, Fleischer B. Dipeptidyl-peptidase IV/CD26 on T cells: analysis of an alternative T-cell activation pathway. Immunol Rev. 1998;161:43–53.

    Article  Google Scholar 

  9. Schreck S, Friebel D, Buettner M, et al. Prognostic impact of tumour-infiltrating Th2 and regulatory cells in classical Hodgkin lymphoma. Hematol Oncol. 2009;27:31–9.

    Article  PubMed  CAS  Google Scholar 

  10. Ma Y, Visser L, Blokzijl T, et al. The CD4+CD26- T-cell population in classical Hodgkin’s lymphoma displays a distinctive regulatory T-cell profile. Lab Invest. 2008;88:482–90.

    Article  PubMed  CAS  Google Scholar 

  11. Munro JM, Freedman AS, Aster JC, et al. In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin’s disease. Blood. 1994;83:793–8.

    PubMed  CAS  Google Scholar 

  12. Atayar C, Poppema S, Visser L, et al. Cytokine gene expression profile distinguishes CD4+/CD57+ T-cells of nodular lymphocyte predominance type of Hodgkin lymphoma from their tonsillar counterparts. J Pathol. 2006;208:423–30.

    Article  PubMed  CAS  Google Scholar 

  13. Rahemtullah A, Harris NL, Dorn ME, et al. Beyond the lymphocyte predominant cell: CD4+CD8+ T-cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma. 2008;49:1870–8.

    Article  PubMed  CAS  Google Scholar 

  14. Ohshima K, Akaiwa M, Umeshita R, et al. Interleukin-13 and interleukin-13 receptor in Hodgkin’s disease: possible autocrine mechanism and involvement in fibrosis. Histopathology. 2001;38:368–75.

    Article  PubMed  CAS  Google Scholar 

  15. Shinozaki M, Kawara S, Hayashi N, et al. Induction of subcutaneous tissue fibrosis in newborn mice by transforming growth factor-b – simultaneous application with basic growth factor causes persistent fibrosis. Biochem Biophys Res Commun. 1997;237:292–6.

    Article  PubMed  CAS  Google Scholar 

  16. Kadin M, Butmarc J, Elovic A, et al. Eosinophils are the major source of transforming growth factor-beta 1 in nodular sclerosing Hodgkin’s disease. Am J Pathol. 1993;142:11–6.

    PubMed  CAS  Google Scholar 

  17. Newcom SR, Gu L. Transforming growth factor beta 1 messenger RNA in Reed–Sternberg cells in nodular sclerosing Hodgkin’s disease. J Clin Pathol. 1995;48:160–3.

    Article  PubMed  CAS  Google Scholar 

  18. Ohshima K, Sugihara M, Suzumiya J, et al. Basic fibroblast growth factor and fibrosis in Hodgkin’s disease. Pathol Res Pract. 1999;195:149–55.

    Article  PubMed  CAS  Google Scholar 

  19. Samoszuk M, Nansen L. Detection of interleukin-5 messenger RNA in Reed-Sernberg cells of Hodgkin’s disease with eosinophilia. Blood. 1990;75:13–6.

    PubMed  CAS  Google Scholar 

  20. Jundt F, Anagnostopoulos I, Bommert K, et al. Hodgkin/Reed–Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood. 1999;94:2065–71.

    PubMed  CAS  Google Scholar 

  21. Hanamoto H, Nakayama T, Miyazato H. Expression of CCL28 by Reed–Sternberg cells defines a major subtype of classical Hodgkin’s disease with frequent infiltration of eosinophils and/or plasma cells. Am J Pathol. 2004;164:997–1006.

    Article  PubMed  CAS  Google Scholar 

  22. Glimelius I, Edstrom A, Amini RM, et al. IL-9 expression contributes to the cellular composition in Hodgkin lymphoma. Eur J Haematol. 2006;76:278–83.

    Article  PubMed  Google Scholar 

  23. Jucker M, Abts H, Li W, et al. Expression of interleukin-6 and interleukin-6 receptor in Hodgkin’s disease. Blood. 1991;77:2413–8.

    PubMed  CAS  Google Scholar 

  24. Goedert JJ, Cote TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet. 1998;351:1833–9.

    Article  PubMed  CAS  Google Scholar 

  25. Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108:3786–91.

    Article  PubMed  CAS  Google Scholar 

  26. Aldinucci D, Poletto D, Nanni P, et al. Expression of functional interleukin-3 receptors on Hodgkin and Reed–Sternberg cells. Am J Pathol. 2002;160:585–96.

    Article  PubMed  CAS  Google Scholar 

  27. Foss HD, Hummel M, Gottstein S, et al. Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin’s disease. Am J Pathol. 1995;146:33–9.

    PubMed  CAS  Google Scholar 

  28. Cattaruzza L, Gloghini A, Olivo K, et al. Functional coexpression of interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed–Sternberg cells: involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin’s lymphoma. Int J Cancer. 2009;125:1092–101.

    Article  PubMed  CAS  Google Scholar 

  29. Kapp U, Yeh WC, Patterson B, et al. Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed–Sternberg cells. J Exp Med. 1999;189:1939–46.

    Article  PubMed  CAS  Google Scholar 

  30. Herbst H, Samol J, Foss HD, et al. Modulation of interleukin-6 expression in Hodgkin and Reed–Sternberg cells by Epstein–Barr virus. J Pathol. 1997;182:299–306.

    Article  PubMed  CAS  Google Scholar 

  31. Pinto A, Aldinucci D, Gloghini A, et al. Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin’s disease cell line. Blood. 1996;88:3299–305.

    PubMed  CAS  Google Scholar 

  32. Molin D, Edstrom A, Glimelius I, et al. Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol. 2002;119:122–4.

    Article  PubMed  Google Scholar 

  33. Grüss HJ, Ulrich D, Braddy S, et al. Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed–Sternberg cells. Eur J Immunol. 1995;25:2083–9.

    Article  PubMed  Google Scholar 

  34. Carbone A, Gloghini A, Gattei V, et al. Expression of functional CD40 antigen on Reed–Sternberg cells and Hodgkin’s disease cell lines. Blood. 1995;85:780–9.

    PubMed  CAS  Google Scholar 

  35. Peh SC, Kim LH, Poppema S. TARC, a CC chemokine, is frequently expressed in classic Hodgkin lymphoma but not in NLP Hodgkin lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma. Am J Surg Pathol. 2001;25:925–9.

    Article  PubMed  CAS  Google Scholar 

  36. Van Den Berg A, Visser L, Poppema S. High expression of the CC chemokine TARC in Reed–Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin’s lymphoma. Am J Pathol. 1999;154:1685–91.

    Article  PubMed  Google Scholar 

  37. Niens M, Visser L, Nolte IM, et al. Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol. 2008;140:527–36.

    Article  PubMed  CAS  Google Scholar 

  38. Weihrauch MR, Manzke O, Beyer M, et al. Elevated levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin’s disease: potential for a prognostic factor. Cancer Res. 2005;65:5516–9.

    Article  PubMed  CAS  Google Scholar 

  39. Ohshima K, Tutiya T, Yamaguchi T, et al. Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&RS) cells in Hodgkin disease: relation with expression of CXC and CC chemokines on H&RS cells. Int J Cancer. 2002;98:567–72.

    Article  PubMed  CAS  Google Scholar 

  40. Ishida T, Ishii T, Inagaki, et al. Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res. 2006;66:5716–22.

    Article  PubMed  CAS  Google Scholar 

  41. Andrew DP, Chang MS, McNinch J, et al. STPC-1 (MDC) CC chemokine acts specifically on chronically activated Th2 lymphocytes and is produced by monocytes on stimulation with Th2 cytokines IL-4 and IL-13. J Immunol. 1998;16:5027–38.

    Google Scholar 

  42. Hedvat CV, Jaffe ES, Qin J, et al. Macrophage-derived chemokine expression in classical Hodgkin’s lymphoma: application of tissue microarrays. Mod Pathol. 2001;14:1270–6.

    Article  PubMed  CAS  Google Scholar 

  43. Imai T, Chantry D, Raport CJ, et al. Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem. 1998;273:1764–8.

    Article  PubMed  CAS  Google Scholar 

  44. Maggio E, van den Berg A, Visser L, et al. Common and differential chemokine expression patterns in RS cells of NLP, EBV positive and negative classical Hodgkin lymphomas. Int J Cancer. 2002;99:665–72.

    Article  PubMed  CAS  Google Scholar 

  45. Lamprecht B, Kreher S, Anagnostopoulos I, et al. Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha. Blood. 2008;112:3339–47.

    Article  PubMed  CAS  Google Scholar 

  46. Tanijiri T, Shimizu T, Uehira K, et al. Hodgkin’s Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4+CD25+Foxp3+ T cells and CD4+ cytotoxic T lymphocytes from CD4+ naïve T cells. J Leukoc Biol. 2007;82:576–84.

    Article  PubMed  CAS  Google Scholar 

  47. Dukers DF, Jaspars LH, Vos W, et al. Quantitative immunohistochemical analysis of cytokine profiles in Epstein–Barr virus-positive and -negative cases of Hodgkin’s disease. J Pathol. 2000;190:143–9.

    Article  PubMed  CAS  Google Scholar 

  48. Herbst H, Foss HD, Samol J, et al. Frequent expression of interleukin-10 by Epstein–Barr virus-harboring tumor cells of Hodgkin’s disease. Blood. 1996;87:2918–29.

    PubMed  CAS  Google Scholar 

  49. Newcom SR, Kadin ME, Ansari AA, et al. L-428 nodular sclerosing Hodgkin’s cell secretes a unique transforming growth factor-beta active at physiologic pH. J Clin Invest. 1988;82:1915–21.

    Article  PubMed  CAS  Google Scholar 

  50. Newcom SR, Tagra KK. High molecular weight transforming growth factor β is excreted in the urine in active nodular sclerosing Hodgkin’s disease. Cancer Res. 1992;52:6768–73.

    PubMed  CAS  Google Scholar 

  51. Marshall NA, Christie LE, Munro LR, et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2004;103:1755–62.

    Article  PubMed  CAS  Google Scholar 

  52. Juszczynski P, Ouyang J, Monti S, et al. the AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2007;104:13134–9.

    Article  PubMed  CAS  Google Scholar 

  53. Maggio EM, van den Berg A, de Jong D, et al. Low frequency of FAS mutations in Reed–Sternberg cells of Hodgkin’s lymphoma. Am J Pathol. 2003;162:29–35.

    Article  PubMed  CAS  Google Scholar 

  54. Yamamoto R, Nishikori M, Kitawaki T, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111:3220–4.

    Article  PubMed  CAS  Google Scholar 

  55. Schwaller J, Tobler A, Niklaus G, et al. Interleukin-12 expression in human lymphomas and nonneoplastic lymphoid disorders. Blood. 1995;85:2182–8.

    PubMed  CAS  Google Scholar 

  56. Niedobitek G, Pazolt D, Teichmann M, et al. Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed–Sternberg cells. J Pathol. 2002;198:310–6.

    Article  PubMed  CAS  Google Scholar 

  57. Keryer-Bibens C, Pioche-Durieu C, Villemant C, et al. Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer. 2006;6:283.

    Article  PubMed  Google Scholar 

  58. Ferraris AM, Racchi O, Rapezzi D, et al. Familial Hodgkin’s disease: a disease of young adulthood? Ann Hematol. 1997;74:131–4.

    Article  PubMed  CAS  Google Scholar 

  59. Glaser SL, Hsu JL. Hodgkin’s disease in Asians: incidence patterns and risk factors in population-based data. Leuk Res. 2002;26:261–9.

    Article  PubMed  Google Scholar 

  60. Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med. 1995;332:413–8.

    Article  PubMed  CAS  Google Scholar 

  61. Diepstra A, Niens M, Vellenga E, et al. Association with HLA class I in Epstein–Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin’s lymphoma. Lancet. 2005;365:2216–24.

    Article  PubMed  CAS  Google Scholar 

  62. Niens M, van den Berg A, Diepstra A, et al. The human leukocyte antigen class I region is associated with EBV-positive Hodgkin’s lymphoma: HLA-A and HLA complex group 9 are putative candidate genes. Cancer Epidemiol Biomarkers Prev. 2006;15:2280–4.

    Article  PubMed  CAS  Google Scholar 

  63. Levitskaya J, Coram M, Levitsky V, et al. Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature. 1995;375:685–8.

    Article  PubMed  CAS  Google Scholar 

  64. Meij P, Leen A, Rickinson AB, et al. Identification and prevalence of CD8(+) T-cell responses directed against Epstein–Barr virus-encoded latent membrane protein 1 and latent membrane protein 2. Int J Cancer. 2002;99:93–9.

    Article  PubMed  CAS  Google Scholar 

  65. Bollard CM, Aguilar L, Straathof KC, et al. Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin’s disease. J Exp Med. 2004;200:1623–33.

    Article  PubMed  CAS  Google Scholar 

  66. Lucas KG, Salzman D, Garcia A, et al. Adoptive immunotherapy with allogeneic Epstein–Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent EBV-positive Hodgkin disease. Cancer. 2004;100:1892–901.

    Article  PubMed  Google Scholar 

  67. Niens M, Jarrett RF, Hepkema B, et al. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood. 2007;110:3310–5.

    Article  PubMed  CAS  Google Scholar 

  68. McAulay KA, Higgins CD, Macsween KF, et al. HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest. 2007;117:3042–8.

    Article  PubMed  CAS  Google Scholar 

  69. Jarrett RF. Viruses and Hodgkin’s lymphoma. Ann Oncol. 2002;13 suppl 1:23–9.

    Article  PubMed  Google Scholar 

  70. Diepstra A, van Imhoff GW, Karim-Kos HE, et al. HLA class II expression by Hodgkin Reed–Sternberg cells is an independent prognostic factor in classical Hodgkin’s lymphoma. J Clin Oncol. 2007;25:3101–8.

    Article  PubMed  Google Scholar 

  71. Ressing ME, Horst D, Griffin BD, et al. Epstein-Barr virus evasion of CD8+ and CD4+ T cell immunity via concerted actions of multiple gene products. Semin Cancer Biol. 2008;18:397–408.

    Article  PubMed  CAS  Google Scholar 

  72. Alvaro T, Lejeune M, Salvado MT, et al. Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005;11:1467–73.

    Article  PubMed  Google Scholar 

  73. Kelley TW, Pohlman B, Elson P, et al. The ratio of Foxp3+ regulatory T cells to Granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression. Am J Clin Pathol. 2007;128:958–65.

    Article  PubMed  Google Scholar 

  74. Oudejans JJ, Jiwa NM, Kummer JA, et al. Activated cytotoxic T cells as prognostic marker in Hodgkin’s disease. Blood. 1997;89:1376–82.

    PubMed  CAS  Google Scholar 

  75. Delabie J, Chan WC, Weisenburger DD, et al. The antigen-presenting cell function of Reed–Sternberg cells. Leuk Lymphoma. 1995;18:35–40.

    Article  PubMed  CAS  Google Scholar 

  76. Diepstra A, Poppema S, Boot M, et al. HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma. Tissue Antigens. 2008;71:219–26.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Lydia Visser, Anke van den Berg, Sibrand Poppema & Arjan Diepstra

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  1. Lydia Visser
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  2. Anke van den Berg
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  3. Sibrand Poppema
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  4. Arjan Diepstra
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Correspondence to Arjan Diepstra .

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Editors and Affiliations

  1. Klinik I für Innere Medizin, Universität Köln, Joseph-Stelzmann-Str. 9, Köln, 50924, Germany

    Andreas Engert

  2. Dept. Medicine, Stanford University, Stanford, 94305-5479, California, USA

    Sandra J. Horning

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Visser, L., van den Berg, A., Poppema, S., Diepstra, A. (2011). Microenvironment, Cross-Talk, and Immune Escape Mechanisms. In: Engert, A., Horning, S. (eds) Hodgkin Lymphoma. Hematologic Malignancies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12780-9_4

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  • DOI: https://doi.org/10.1007/978-3-642-12780-9_4

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