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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

Hodgkin lymphoma is a unique malignancy in which reactive immune cells vastly outnumber the tumor cells. The microenvironment is essential in many different aspects of Hodgkin lymphoma biology and has ramifications for diagnosis, clinical presentation, and therapeutic options. In this chapter we review current knowledge on the Hodgkin lymphoma microenvironment. Its composition is highly variable and provides the basis for diagnostic subtyping. T cells are virtually always present and usually cluster together with the tumor cells in so-called rosettes. We describe mechanisms by which the tumor cells actively shape their cellular environment and how this ensures recruitment of tumor cell promoting growth factors. The tumor cells also need to employ a variety of immune escape mechanisms with a central role for antigen presentation through the human leukocyte antigen and associated immune checkpoints. Given the different pathogenetic functions of different cell types in the microenvironment, we end with reviewing data on the prognostic impact of the abundance of specific cell types.

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References

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

    Google Scholar 

  2. Stein H, Delsol G, Pileri SA et al (2016) Classical Hodgkin lymphoma, introduction. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, Lyon

    Google Scholar 

  3. Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke RA (2003) Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 27:1346–1356

    Article  PubMed  Google Scholar 

  4. Atayar C, van den Berg A, Blokzijl T et al (2007) Hodgkin lymphoma associated T-cells exhibit a transcription factor profile consistent with distinct lymphoid compartments. J Clin Pathol 60:1092–1097

    Article  PubMed  Google Scholar 

  5. Carbone A, Gloghini A, Cabras A et al (2009) Differentiating germinal center-derived lymphomas through their cellular microenvironment. Am J Hematol 84:435–438

    Article  CAS  PubMed  Google Scholar 

  6. Sattarzadeh A, Visser L, Rutgers B, Diepstra A, van den Berg A (2016) Characterization of the microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma. Int J Mol Sci 17:e2127

    Article  PubMed  CAS  Google Scholar 

  7. Huppmann AR, Nicolae A, Slack GW et al (2014) EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38:316–324

    Article  PubMed  PubMed Central  Google Scholar 

  8. Oudejans JJ, Jiwa NM, Kummer JA et al (1996) Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr virus-positive and -negative Hodgkin’s disease. Blood 87:3844–3851

    Article  CAS  PubMed  Google Scholar 

  9. Goedert JJ, Cote TR, Virgo P et al (1998) Spectrum of AIDS-associated malignant disorders. Lancet 351:1833–1839

    Article  CAS  PubMed  Google Scholar 

  10. Biggar RJ, Jaffe ES, Goedert JJ et al (2006) Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108:3786–3791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Poppema S (1996) Immunology of Hodgkin’s disease. Ballieres Clin Haematol 9:447–457

    Article  CAS  Google Scholar 

  12. Wolf M, Albrecht S, Marki C (2008) Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int J Biochem Cell Biol 40:1185–1198

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  14. Schreck S, Friebel D, Buettner M et al (2009) Prognostic impact of tumour-infiltrating Th2 and regulatory cells in classical Hodgkin lymphoma. Hematol Oncol 27:31–39

    Article  CAS  PubMed  Google Scholar 

  15. Ma Y, Visser L, Blokzijl T et al (2008) The CD4+CD26− T-cell population in classical Hodgkin’s lymphoma displays a distinctive regulatory T-cell profile. Lab Investig 88:482–490

    Article  CAS  PubMed  Google Scholar 

  16. Greaves P, Clear A, Owen A et al (2013) Defining characteristics of classical Hodgkin lymphoma microenvironment T helper cells. Blood 122:2856–2863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu R, Sattarzadeh A, Rutgers B, Diepstra A, van den Berg A, Visser L (2016) The microenvironment of classical Hodgkin lymphoma: heterogeneity by Epstein-Barr virus presence and location within the tumor. Blood Cancer J 6:e417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cader FZ, Schackmann RCJ, Hu X et al (2018) Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment. Blood 132:825–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nam-Cha SH, Roncador G, Sanchez-Verde L et al (2008) PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma. Am J Surg Pathol 32:1252–1257

    Article  PubMed  Google Scholar 

  20. Sattarzadeh A, Diepstra A, Rutgers B, van den Berg A, Visser L (2015) CD57+ T-cells are a subpopulation of T-follicular helper cells in nodular lymphocyte-predominant Hodgkin lymphoma. Exp Hematol Oncol 4:27

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Atayar C, Poppema S, Visser L et al (2006) Cytokine gene expression profile distinguishes CD4+/CD57+ T-cells of nodular lymphocyte predominance type of Hodgkin lymphoma from their tonsillar counterparts. J Pathol 208:423–430

    Article  CAS  PubMed  Google Scholar 

  22. Rahemtullah A, Harris NL, Dorn ME et al (2008) Beyond the lymphocyte predominant cell: CD4+CD8+ T-cells in nodular lymphocyte predominant Hodgkin lymphoma. Leuk Lymphoma 49:1870–1878

    Article  CAS  PubMed  Google Scholar 

  23. Ohshima K, Akaiwa M, Umeshita R et al (2001) Interleukin-13 and interleukin-13 receptor in Hodgkin’s disease: possible autocrine mechanism and involvement in fibrosis. Histopathology 38:368–375

    Article  CAS  PubMed  Google Scholar 

  24. Shinozaki M, Kawara S, Hayashi N et al (1997) 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 237:292–296

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Newcom SR, Gu L (1995) Transforming growth factor beta 1 messenger RNA in Reed-Sternberg cells in nodular sclerosing Hodgkin’s disease. J Clin Pathol 48:160–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ohshima K, Sugihara M, Suzumiya J et al (1999) Basic fibroblast growth factor and fibrosis in Hodgkin’s disease. Pathol Res Pract 195:149–155

    Article  CAS  PubMed  Google Scholar 

  28. Samoszuk M, Nansen L (1990) Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin’s disease with eosinophilia. Blood 75:13–16

    Article  CAS  PubMed  Google Scholar 

  29. Jundt F, Anagnostopoulos I, Bommert K et al (1999) Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 94:2065–2071

    Article  CAS  PubMed  Google Scholar 

  30. Hanamoto H, Nakayama T, Miyazato H (2004) 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 164:997–1006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Glimelius I, Edstrom A, Amini RM et al (2006) IL-9 expression contributes to the cellular composition in Hodgkin lymphoma. Eur J Haematol 76:278–283

    Article  PubMed  Google Scholar 

  32. Jucker M, Abts H, Li W et al (1991) Expression of interleukin-6 and interleukin-6 receptor in Hodgkin’s disease. Blood 77:2413–2418

    Article  CAS  PubMed  Google Scholar 

  33. Tudor CS, Distel LV, Eckhardt J et al (2013) B cells in classical Hodgkin lymphoma are important actors rather than bystanders in the local immune reaction. Hum Pathol 44:2475–2486

    Article  CAS  PubMed  Google Scholar 

  34. Aldinucci D, Poletto D, Nanni P et al (2002) Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells. Am J Pathol 160:585–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Foss HD, Hummel M, Gottstein S et al (1995) Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin’s disease. Am J Pathol 146:33–39

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Cattaruzza L, Gloghini A, Olivo K et al (2009) 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 125:1092–1101

    Article  CAS  PubMed  Google Scholar 

  37. Kapp U, Yeh WC, Patterson B et al (1999) Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 189:1939–1946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ullrich K, Blumenthal-Barby F, Lamprecht B et al (2015) The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells. Leukemia 29:1213–1218

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Cochet O, Frelin C, Peyron J-F, Imbert V (2006) Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal 18:449–455

    Article  CAS  PubMed  Google Scholar 

  41. Kube D, Holtick U, Vockerodt M et al (2001) STAT3 is constitutively activated in Hodgkin cell lines. Blood 98:762–770

    Article  CAS  PubMed  Google Scholar 

  42. Hinz M, Lemke P, Anagnostopoulos I, Hacker C et al (2002) Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 196:605–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Skinnider BF, Elia AJ, Gascoyne RD et al (2002) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99:618–626

    Article  CAS  PubMed  Google Scholar 

  44. Green MR, Rodig S, Juszczynski P et al (2012) Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders; implications for targeted therapy. Clin Cancer Res 18:1611–1618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Baus D, Pfitzner E (2006) Specific function of STAT3, SOCS1, and SOCS3 in the regulation of proliferation and survival of classical Hodgkin lymphoma cells. Int J Cancer 118:1404–1413

    Article  CAS  PubMed  Google Scholar 

  46. Baus D, Nonnenmacher F, Jankowski S et al (2009) STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line. Leukemia 23:1885–1893

    Article  CAS  PubMed  Google Scholar 

  47. Scheeren FA, Diehl SA, Smit LA et al (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111:4709–4715

    Article  CAS  Google Scholar 

  48. Pinto A, Aldinucci D, Gloghini A et al (1996) Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin’s disease cell line. Blood 88:3299–3305

    Article  CAS  PubMed  Google Scholar 

  49. Molin D, Edstrom A, Glimelius I et al (2002) Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 119:122–124

    Article  PubMed  Google Scholar 

  50. Grüss HJ, Ulrich D, Braddy S et al (1995) Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells. Eur J Immunol 25:2083–2089

    Article  PubMed  Google Scholar 

  51. Carbone A, Gloghini A, Gattei V et al (1995) Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin’s disease cell lines. Blood 85:780–789

    Article  CAS  PubMed  Google Scholar 

  52. Renné C, Willenbrock K, Küppers R et al (2005) Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. Blood 105:4051–4059

    Article  PubMed  CAS  Google Scholar 

  53. Cader FZ, Vockerodt M, Bose S et al (2013) The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 122:4237–4245

    Article  CAS  PubMed  Google Scholar 

  54. Renné C, Minner S, Küppers R et al (2008) Autocrine NGFβ/TRKA signaling is an important survival factor for Hodgkin lymphoma derived cell lines. Leukemia Res 32:163–167

    Article  CAS  Google Scholar 

  55. Xu C, Plattel W, van den Berg A et al (2012) Expression of the c-met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin’s lymphoma. Heamatologica 97:572–578

    Article  CAS  Google Scholar 

  56. Liang Z, Diepstra A, Xu C et al (2014) Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma. PLOSone 9:e87474

    Article  CAS  Google Scholar 

  57. Eppler E, Janas E, Link K et al (2015) Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin’s lymphoma tumour and microenvironmental cells. Cell Tissue Res 359:841–851

    Article  CAS  PubMed  Google Scholar 

  58. Renné C, Hinsch N, Willenbrock K et al (2007) The aberrant coexpression of several receptor tyrosine kinases is largely restricted to EBV-negative cases of classical Hodgkin’s lymphoma. Int J Cancer 120:2504–2509

    Article  PubMed  CAS  Google Scholar 

  59. Schwarzer R, Dörken B, Jundt F (2012) Notch is an essential upstream regulator of NF-κB and is relevant for the survival of Hodgkin and Reed-Sternberg cells. Leukemia 26:806–813

    Article  CAS  PubMed  Google Scholar 

  60. Jundt F, Anagnostopoulos I, Förster R et al (2002) Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 99:3398–3403

    Article  CAS  PubMed  Google Scholar 

  61. Peh SC, Kim LH, Poppema S (2001) 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 25:925–929

    Article  CAS  PubMed  Google Scholar 

  62. Van den Berg A, Visser L, Poppema S (1999) 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 154:1685–1691

    Article  PubMed  PubMed Central  Google Scholar 

  63. Niens M, Visser L, Nolte IM et al (2008) Serum chemokine levels in Hodgkin lymphoma patients: highly increased levels of CCL17 and CCL22. Br J Haematol 140:527–536

    Article  CAS  PubMed  Google Scholar 

  64. Weihrauch MR, Manzke O, Beyer M et al (2005) Elevated levels of CC thymus and activation-related chemokine (TARC) in primary Hodgkin’s disease: potential for a prognostic factor. Cancer Res 65:5516–5519

    Article  CAS  PubMed  Google Scholar 

  65. Plattel WJ, van den Berg A, Visser L et al (2012) Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin’s lymphoma. Haematologica 97:410–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sauer M, Plütschow A, Jachimowicz RD et al (2013) Baseline serum TARC levels predict therapy outcome in patients with Hodgkin lymphoma. Am J Hematol 88:113–115

    Article  CAS  PubMed  Google Scholar 

  67. Plattel WJ, Alsada ZN, van Imhoff GW, Diepstra A, van den Berg A, Visser L (2016) Biomarkers for evaluation of treatment response in classical Hodgkin lymphoma: comparison of sGalectin-1, sCD163 and sCD30 with TARC. Br J Haematol 175(5):868–875

    Article  CAS  PubMed  Google Scholar 

  68. Ohshima K, Tutiya T, Yamaguchi T et al (2002) 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 98:567–572

    Article  CAS  PubMed  Google Scholar 

  69. Ishida T, Ishii T, Inagaki A et al (2006) Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 66:5716–5722

    Article  CAS  PubMed  Google Scholar 

  70. Andrew DP, Chang MS, McNinch J et al (1998) 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 16:5027–5038

    Google Scholar 

  71. Hedvat CV, Jaffe ES, Qin J et al (2001) Macrophage-derived chemokine expression in classical Hodgkin’s lymphoma: application of tissue microarrays. Mod Pathol 14:1270–1276

    Article  CAS  PubMed  Google Scholar 

  72. Imai T, Chantry D, Raport CJ et al (1998) Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J Biol Chem 273:1764–1768

    Article  CAS  PubMed  Google Scholar 

  73. Maggio E, van den Berg A, Visser L et al (2002) Common and differential chemokine expression patterns in RS cells of NLP, EBV positive and negative classical Hodgkin lymphomas. Int J Cancer 99:665–672

    Article  CAS  PubMed  Google Scholar 

  74. Lamprecht B, Kreher S, Anagnostopoulos I et al (2008) 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 112:3339–3347

    Article  CAS  PubMed  Google Scholar 

  75. Morales O, Mrizak D, François V et al (2014) Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol 166:875–890

    Article  CAS  PubMed  Google Scholar 

  76. Fhu CW, Graham AM, Yap CT et al (2014) Reed-Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma. Blood 124:2973–2982

    Article  CAS  PubMed  Google Scholar 

  77. Foss H-D, Herbst H, Oelmann E et al (1993) Lymphotoxin, tumour necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin’s disease cases. Br J Haematol 84:627–635

    Article  CAS  PubMed  Google Scholar 

  78. Tanijiri T, Shimizu T, Uehira K et al (2007) 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+ naive T cells. J Leukoc Biol 82:576–584

    Article  CAS  PubMed  Google Scholar 

  79. Ferraris AM, Racchi O, Rapezzi D et al (1997) Familial Hodgkin’s disease: a disease of young adulthood? Ann Hematol 74:131–134

    Article  CAS  PubMed  Google Scholar 

  80. Glaser SL, Hsu JL (2002) Hodgkin’s disease in Asians: incidence patterns and risk factors in population-based data. Leuk Res 26:261–269

    Article  PubMed  Google Scholar 

  81. Mack TM, Cozen W, Shibata DK et al (1995) Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med 332:413–418

    Article  CAS  PubMed  Google Scholar 

  82. Diepstra A, Niens M, Vellenga E et al (2005) Association with HLA class I in Epstein–Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin’s lymphoma. Lancet 365:2216–2224

    Article  CAS  PubMed  Google Scholar 

  83. Niens M, van den Berg A, Diepstra A et al (2006) 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 Biomark Prev 15:2280–2284

    Article  CAS  Google Scholar 

  84. Enciso-Mora V, Broderick PMY et al (2010) A genome-wide association study of Hodgkin’s lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42:1126–1130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Urayama KY, Jarrett RF, Hjalgrim H et al (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 104:240–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Cozen W, Li D, Best T et al (2012) A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119:469–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sud A, Thomsen H, Orlando G et al (2018) Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma. Blood 132:1212–1218

    Article  Google Scholar 

  88. Levitskaya J, Coram M, Levitsky V et al (1995) Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375:685–688

    Article  CAS  PubMed  Google Scholar 

  89. Meij P, Leen A, Rickinson AB et al (2002) 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 99:93–99

    Article  CAS  PubMed  Google Scholar 

  90. Bollard CM, Aguilar L, Straathof KC et al (2004) Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin’s disease. J Exp Med 200:1623–1633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lucas KG, Salzman D, Garcia A et al (2004) Adoptive immunotherapy with allogeneic Epstein–Barr virus (EBV)-specific cytotoxic T-lymphocytes for recurrent EBV-positive Hodgkin disease. Cancer 100:1892–1901

    Article  PubMed  Google Scholar 

  92. Bollard CM, Gottschalk S, Torrano V et al (2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32:798–808

    Article  CAS  PubMed  Google Scholar 

  93. Niens M, Jarrett RF, Hepkema B et al (2007) HLA-A∗02 is associated with a reduced risk and HLA-A∗01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 110:3310–3315

    Article  CAS  PubMed  Google Scholar 

  94. Jones K, Wockner L, Brennan RM et al (2016) The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma. Clin Exp Immunol 183:206–220

    Article  CAS  PubMed  Google Scholar 

  95. Diepstra A, van Imhoff GW, Karim-Kos HE et al (2007) HLA class II expression by Hodgkin Reed-Sternberg cells is an independent prognostic factor in classical Hodgkin’s lymphoma. J Clin Oncol 25:3101–3108

    Article  PubMed  Google Scholar 

  96. Nijland M, Veenstra RN, Visser L et al (2017) HLA dependent immune escape mechanisms in B-cell lymphomas: implications for immune checkpoint inhibitor therapy? Oncoimmunology e1295202:6

    Google Scholar 

  97. Reichel J, Chadburn A, Rubinstein PG et al (2015) Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 125:1061–1072

    Article  CAS  PubMed  Google Scholar 

  98. Diepstra A, Poppema S, Boot M et al (2008) HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma. Tissue Antigens 71:219–226

    Article  CAS  PubMed  Google Scholar 

  99. Zocchi MR, Catellani S, Canevali P et al (2012) High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 119:1479–1489

    Article  CAS  PubMed  Google Scholar 

  100. Steidl C, Shah SP, Woolcock BW et al (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471:377–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Walunas TL, Lenschow DJ, Bakker CY et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413

    Article  CAS  PubMed  Google Scholar 

  102. Alegre M, Frauwirth KA (2001) Thompson CB. T cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1:220–228

    Article  CAS  PubMed  Google Scholar 

  103. Bashey A, Medina B, Corringham S et al (2009) CTLA-4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Davids MS, Kim HT, Bachireddy P et al (2016) Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 375:143–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yamamoto R, Nishikori M, Kitawaki T et al (2008) PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 15(111):3220–3224

    Article  CAS  Google Scholar 

  106. Vari F, Arpon D, Keane C et al (2018) Immune evasion via PD-1/PD-L1 on NK-cells and monocytes/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 131:1809–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Green MR, Monti S, Rodig SJ et al (2010) Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell. Blood 116:3268–3277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ansell SM, Lesokhin AM, Borrello I et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319

    Article  PubMed  CAS  Google Scholar 

  109. Armand P, Engert A, Younes A et al (2018) Nivolumab for relapsed/refractory classical Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol 36:1428–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Younes A, Santoro A, Shipp M et al (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283–1294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Chen R, Zinzani PL, Fanale MA et al (2017) Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35:2125–2132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tumeh PC, Harview CL, Yearley JH et al (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Carey CD, Gusenleitner D, Lipschitz M et al (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420–2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Roemer MGM, Redd RA, Cader FZ et al (2018) Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death blockade in classical Hodgkin lymphoma. J Clin Oncol 36:942–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Muenst S, Hoeller S, Dirnhofer S et al (2009) Increased programmed death-1+ tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival. Hum Pathol 40:1715–1722

    Article  CAS  PubMed  Google Scholar 

  116. Goldberg MV, Drake CG (2011) LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol 344:269–278

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Huard B, Prigent P, Tournier M et al (1995) CD4/major histocompatibility complex class II interaction analyzed with CD4− and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 25:2718–2721

    Article  CAS  PubMed  Google Scholar 

  118. Gandhi MK, Lambley E, Duraiswamy J et al (2006) Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 108:2280–2289

    Article  CAS  PubMed  Google Scholar 

  119. Camisaschi C, Casati C, Rini F et al (2010) LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 184:6545–6551

    Article  CAS  PubMed  Google Scholar 

  120. Duffield AS, Ascierto ML, Anders RA et al (2017) Th17 immune microenvironment in Epstein-Barr virus-negative Hodgkin lymphoma: implications for immunotherapy. Blood Adv 1:1324–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wein F, Weniger MA, Höing B et al (2017) Complex immune evasion strategies in classical Hodgkin lymphoma. Cancer Immunol Res 5:1122–1132

    Article  CAS  PubMed  Google Scholar 

  122. Dukers DF, Jaspars LH, Vos W et al (2000) Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin’s disease. J Pathol 190:143–149

    Article  CAS  PubMed  Google Scholar 

  123. Herbst H, Foss HD, Samol J et al (1996) Frequent expression of interleukin-10 by Epstein–Barr virus-harboring tumor cells of Hodgkin’s disease. Blood 87:2918–2929

    Article  CAS  PubMed  Google Scholar 

  124. Newcom SR, Kadin ME, Ansari AA et al (1988) L-428 nodular sclerosing Hodgkin’s cell secretes a unique transforming growth factor-beta active at physiologic pH. J Clin Invest 82:1915–1921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Newcom SR, Tagra KK (1992) High molecular weight transforming growth factor b is excreted in the urine in active nodular sclerosing Hodgkin’s disease. Cancer Res 52:6768–6773

    CAS  PubMed  Google Scholar 

  126. Marshall NA, Christie LE, Munro LR et al (2004) Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762

    Article  CAS  PubMed  Google Scholar 

  127. Juszczynski P, Ouyang J, Monti S et al (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 104:13134–13139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gandhi MK, Moll G, Smith C et al (2015) Brief report Galectin-1 mediated suppression of Epstein-Barr virus—specific T-cell immunity in classic Hodgkin lymphoma. Blood 110:1326–1330

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Choe J-Y, Yun JY, Jeon YK et al (2014) Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC Cancer 14:335

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Soliman H, Mediavilla-Varela M, Antonia S (2010) Indoleamine 2,3-dioxygenase. Is i tan immune suppressor? Cancer J 16:354–359

    Article  CAS  PubMed  Google Scholar 

  132. Schwaller J, Tobler A, Niklaus G et al (1995) Interleukin-12 expression in human lymphomas and nonneoplastic lymphoid disorders. Blood 85:2182–2188

    Article  CAS  PubMed  Google Scholar 

  133. Niedobitek G, Pazolt D, Teichmann M et al (2002) 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 198:310–316

    Article  CAS  PubMed  Google Scholar 

  134. Steidl C, Lee T, Shah SP et al (2010) Tumor-associated macrophages and survival in classical Hodgkin’s lymphoma. N Engl J Med 362:875–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Guo B, Cen H, Tan X, Ke Q (2016) Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med 14:159

    Article  PubMed  PubMed Central  Google Scholar 

  136. Barros MHM, Segges P, Vera-Lozada G, Hassan R, Niedobitek G (2015) Macrophage polarization reflects T cell composition of tumor microenvironment in pediatric classical Hodgkin lymphoma and has impact on survival. PLoS One 10:1–19

    CAS  Google Scholar 

  137. Hollander P, Rostgaard K, Smedby KE et al (2017) An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome. Eur J Haematol 100:88–97

    Article  PubMed  CAS  Google Scholar 

  138. Andersen MD, Kamper P, Nielsen PS et al (2016) Tumour-associated mast cells in classical Hodgkin’s lymphoma: correlation with histological subtype, other tumour-infiltrating inflammatory cell subsets and outcome. Eur J Haematol 96:252–259

    Article  CAS  PubMed  Google Scholar 

  139. Alvaro T, Lejeune M, Salvado MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473

    Article  PubMed  Google Scholar 

  140. Kelley TW, Pohlman B, Elson P et al (2007) 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 128:958–965

    Article  PubMed  Google Scholar 

  141. Oudejans JJ, Jiwa NM, Kummer JA et al (1997) Activated cytotoxic T cells as prognostic marker in Hodgkin’s disease. Blood 89:1376–1382

    Article  CAS  PubMed  Google Scholar 

  142. Alonso-Álvarez S, Vidriales MB, Caballero MD et al (2017) The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy. Leuk Lymphoma 58:1144–1152

    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, Johanna Veldman, Sibrand Poppema, Anke van den Berg & Arjan Diepstra

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

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  1. Department of Internal Medicine, University Hospital Cologne, Köln, Nordrhein-Westfalen, Germany

    Andreas Engert

  2. Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Anas Younes

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Visser, L., Veldman, J., Poppema, S., van den Berg, A., Diepstra, A. (2020). Microenvironment, Cross-Talk, and Immune Escape Mechanisms. In: Engert, A., Younes, A. (eds) Hodgkin Lymphoma. Hematologic Malignancies. Springer, Cham. https://doi.org/10.1007/978-3-030-32482-7_4

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