Targeting the Microenvironment in Hodgkin Lymphoma: Opportunities and Challenges

Part of the Molecular Pathology Library book series (MPLB)


The tumor cells in Hodgkin lymphoma (HL) constitute a minority of the affected tissue, while the microenvironment constitutes more than 95% of the total cell population. It has become evident that the infiltrating cells are not just innocent bystanders but active players involved in the pathogenesis of HL. The apparent dependence of the tumor cells on cells present in the microenvironment indicates the potential for therapeutic intervention aiming at targeting specific cell types or factors in the microenvironment. This can be achieved by inhibiting tumor cell-supporting signals or eliminating suppressive factors of the antitumor immune response. In this chapter we will summarize the individual components of the microenvironment, their relevance for tumor cell survival, and possible therapeutic interventions aiming at shifting the balance from a tumor cell-supporting toward a tumor cell-killing microenvironment.


Hodgkin lymphoma Microenvironment Immune escape Antitumor immune responses Immune checkpoint Therapy 





CC chemokine


Class II transactivator


cAMP response element-binding protein-binding protein


Connective tissue growth factor


Cytotoxic T-lymphocyte-associated protein 4


Cytotoxic T cells


CXC chemokine


Discoidin domain receptor tyrosine kinase




Diffuse large B-cell lymphoma


Epstein-Barr nuclear antigen


Epstein-Barr virus


Ephrin type-B receptor 1


Histone deacetylases


Hepatocyte growth factor


Classical Hodgkin lymphoma


Human leukocyte antigen


Hodgkin and Reed-Sternberg


Heat shock protein


Human antigen R






Lymphocyte-activation protein 3


Lymphocyte function-associated antigen


Latent membrane protein


Lymphocyte-predominant tumor




Melanoma-associated antigen 4


Mitogen-activated protein kinase




Nuclear factor-kappa B


Nerve growth factor


NF-κB-inducing kinase


Natural killer


NK cell receptor D


Nodular lymphocyte-predominant Hodgkin lymphoma


Nodular sclerosis


Objective response rate


Programmed cell death protein 1


Platelet-derived growth factor receptor alpha


Primary mediastinal large B-cell lymphoma


Preferentially expressed antigen in melanoma


Protein tyrosine phosphatase, non-receptor type 1




Recepteur d’origine nantais


Receptor tyrosine kinases


Suppressor of cytokine signaling


Synovial sarcoma X


T follicular helper


Transforming growth factor


T helper


T-cell immunoglobulin and mucin-domain containing-3


Tumor necrosis factor


TNF alpha-induced protein 3


Tumor necrosis factor receptor superfamily


T regulatory 1


TNF receptor-associated factor


T regulatory cell


Tropomyosin receptor kinase


  1. Abdul Razak FR, Diepstra A, Visser L, van den Berg A (2016) CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse. Genes Immun 17(6):363PubMedCrossRefGoogle Scholar
  2. Aldinucci D, Poletto D, Gloghini A, Nanni P, Degan M, Perin T et al (2002) Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells. Am J Pathol 160:585–596PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aldinucci D, Lorenzon D, Cattaruzza L, Pinto A, Gloghini A, Carbone A et al (2008) Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: Involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. Int J Cancer 122:769–776PubMedCrossRefGoogle Scholar
  4. Alvaro T, Lejeune M, Salvado MT, Bosch R, García JF, Jaén J et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 11:1467–1473PubMedCrossRefGoogle Scholar
  5. Amant F, Verheecke M, Wlodaska I, Dehaspe L, Brady P, Brison N et al (2015) Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing. JAMA Oncol 1:814–819PubMedCrossRefGoogle Scholar
  6. Andersen MD, Kamper P, Nielsen PS, Bendix K, Riber-Hansen R, Steiniche T 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 96:252–259PubMedCrossRefGoogle Scholar
  7. Anderson MW, Zhao S, Freud AG, Czerwinski DK, Kohrt H, Alizadeh AA et al (2012) CD137 is expressed in follicular dendritic cell tumors and in classical Hodgkin and T-cell lymphomas: Diagnostic and therapeutic implications. Am J Pathol 181:795–803PubMedPubMedCentralCrossRefGoogle Scholar
  8. Annunziata CM, Safiran YJ, Irving SG, Kasid UN, Cossman J (2000) Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor. Blood 96:2841–2848PubMedGoogle Scholar
  9. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319PubMedCrossRefGoogle Scholar
  10. Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J et al (2016) Programmed death-1 with pembrlizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 34:3733–3739CrossRefGoogle Scholar
  11. 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:e0124531PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bashey A, Medina B, Corringham S, Pasek M, Carrier E, Vrooman L et al (2009) CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113:1581–1588PubMedPubMedCentralCrossRefGoogle Scholar
  13. Baumforth KR, Birgersdotter A, Reynolds GM, Wei W, Kapatai G, Flavell JR et al (2008) Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells. Am J Pathol 173:195–204PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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 118:1404–1413PubMedCrossRefGoogle Scholar
  15. Baus D, Nonnenmacher F, Jankowski S, Döring C, Bräutigam C, Frank M et al (2009) STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line. Leukemia 23:1885–1893PubMedCrossRefGoogle Scholar
  16. Birgersdotter A, Baumforth KR, Wei W, Murray PG, Sjöberg J, Björkholm M et al (2010) Connective tissue growth factor is expressed in malignant cells of Hodgkin lymphoma but not in other mature B-cell lymphomas. Am J Clin Pathol 133:271–280PubMedCrossRefGoogle Scholar
  17. Bollard CM, Straathof KC, Huls MH, Leen A, Lacuesta K, Davis A et al (2004) The generation and characterization of LMP2-specific CTLs for use as adoptive transfer from patients with relapsed EBV-positive Hodgkin disease. J Immunother 27:317–327PubMedCrossRefGoogle Scholar
  18. Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y 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 32:798–808PubMedCrossRefGoogle Scholar
  19. Buglio D, Georgakis GV, Hanabuchi S, Arima K, Khaskhely NM, Liu YJ et al (2008) Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines. Blood 112:1424–1433PubMedPubMedCentralCrossRefGoogle Scholar
  20. Buglio D, Mamidipudi V, Khaskhely NM, Brady H, Heise C, Besterman J et al (2010) The class-I HDAC inhibitor MGCD0103 induces apoptosis in Hodgkin lymphoma cell lines and synergizes with proteasome inhibitors by an HDAC6-independent mechanism. Br J Haematol 151:387–396PubMedPubMedCentralCrossRefGoogle Scholar
  21. Buglio D, Khaskhely NM, Voo KS, Martinez-Valdez H, Liu YJ, Younes A (2011) HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma. Blood 117:2910–2917PubMedPubMedCentralCrossRefGoogle Scholar
  22. Buri C, Korner M, Scharli P, Cefai D, Uguccioni M, Mueller C et al (2001) CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease. Blood 97:1543–1548PubMedCrossRefGoogle Scholar
  23. Butterbach K, Beckmann L, de Sanjose S, Benavente Y, Becker N, Foretova L et al (2011) Association of JAK-STAT pathway related genes with lymphoma risk: results of a European case-control study (EpiLymph). Br J Haematol 153:318–333PubMedCrossRefGoogle Scholar
  24. Carbone A, Gloghini A, Gruss HJ, Pinto A (1995) CD40 ligand is constitutively expressed in a subset of T cell lymphomas and on the microenvironmental reactive T cells of follicular lymphomas and Hodgkin’s disease. Am J Pathol 147:912–922PubMedPubMedCentralGoogle Scholar
  25. Cattaruzza L, Gloghini A, Olivo K, Di Francia R, Lorenzon D, De Filippi R 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 125:1092–1101PubMedCrossRefGoogle Scholar
  26. Cedeno-Laurent F, Opperman M, Barthel SR, Kuchroo VK, Dimitroff CJ (2012) Galectin-1 triggers an immunoregulatory signature in Th cells functionally defined by IL-10 expression. J Immunol 188:3127–3137PubMedPubMedCentralCrossRefGoogle Scholar
  27. Celegato M, Borghese C, Umezawa K, Casagrande N, Colombatti A, Carbone A et al (2014a) The NF-kappaB inhibitor DHMEQ decreases survival factors, overcomes the protective activity of microenvironment and synergizes with chemotherapy agents in classical Hodgkin lymphoma. Cancer Lett 349:26–34PubMedCrossRefGoogle Scholar
  28. Celegato M, Borghese C, Casagrande N, Carbone A, Colombatti A, Aldinucci D (2014b) Bortezomib down-modulates the survival factor interferon regulatory factor 4 in Hodgkin lymphoma cell lines and decreases the protective activity of Hodgkin lymphoma-associated fibroblasts. Leuk Lymphoma 55:149–159PubMedCrossRefGoogle Scholar
  29. Celegato M, Borghese C, Casagrande N, Mongiat M, Kahle XU, Paulitti A et al (2015) Preclinical activity of the repurposed drug auranofin in classical Hodgkin lymphoma. Blood 126:1394–1397PubMedPubMedCentralCrossRefGoogle Scholar
  30. Challa-Malladi M, Lieu YK, Califano O, Holmes AB, Bhagat G, Murty VV et al (2011) Combined genetic inactivation of beta2-microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20:728–740PubMedPubMedCentralCrossRefGoogle Scholar
  31. Chang K, Karnad A, Zhao S, Freeman JW (2015) Roles of c-met and RON kinases in tumor progression and their potential as therapeutic targets. Oncotarget 6:3507–3518PubMedPubMedCentralCrossRefGoogle Scholar
  32. Chang D-K, Peterson E, Sun J, Goudie C, Drapkin RI, Liu JF et al (2016) Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology 5:e1090075PubMedCrossRefGoogle Scholar
  33. Chetaille B, Bertucci F, Finetti P, Esterni B, Stamatoullas A, Picquenot JM et al (2009) Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood 113:2765–2775PubMedCrossRefGoogle Scholar
  34. Chong LC, Twa DDW, Mottok A, Ben-Neriah S, Woolcock BW, Zhao Y et al (2016) Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 128:1206–1213PubMedCrossRefGoogle Scholar
  35. Cochet O, Frelin C, Peyron JF, Imbert V (2006) Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal 18:449–455PubMedCrossRefGoogle Scholar
  36. Copeland A, Buglio D, Younes A (2010) Histone deacetylase inhibitors in lymphoma. Curr Opin Oncol 22:431–436PubMedCrossRefGoogle Scholar
  37. Cozen W, Hamilton AS, Zhao P, Salam MT, Deapen DM, Nathwani BN et al (2009) A protective role for early oral exposures in the etiology of young adult Hodgkin lymphoma. Blood 114:4014–4020PubMedPubMedCentralCrossRefGoogle Scholar
  38. Cozen W, Li D, Best T, Van Den Berg DJ, Gourraud PA, Cortessis VK et al (2012) A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119:469–475PubMedPubMedCentralCrossRefGoogle Scholar
  39. Cozen W, Timofeeva MN, Li D, Diepstra A, Hazelett D, Delahaye-Sourdeix M et al (2014) A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun 5:3856PubMedPubMedCentralCrossRefGoogle Scholar
  40. Crocker J, Smith PJ (1984) A quantitative study of mast cells in Hodgkin’s disease. J Clin Pathol 37:519–522PubMedPubMedCentralCrossRefGoogle Scholar
  41. Cruz CR, Gerdemann U, Leen AM, Shafer JA, Ku S, Tzou B et al (2011) Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4. Clin Cancer Res 17:7058–7066PubMedPubMedCentralCrossRefGoogle Scholar
  42. Dengler TJ, Hoffmann JC, Knolle P, Albert-Wolf M, Roux M, Wallich R et al (1992) Structural and functional epitopes of the human adhesion receptor CD58 (LFA-3). Eur J Immunol 22:2809–2817PubMedCrossRefGoogle Scholar
  43. Derenzini E, Lemoine M, Buglio D, Katayama H, Ji Y, Davis RE et al (2011) The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphoma. Blood Cancer J 1:e46PubMedPubMedCentralCrossRefGoogle Scholar
  44. Diaz T, Navarro A, Ferrer G, Gel B, Gaya A, Artells R et al (2011) Lestaurtinib inhibition of the JAK/STAT signaling pathway in Hodgkin lymphoma inhibits proliferation and induces apoptosis. PLoS One 6:e18856PubMedPubMedCentralCrossRefGoogle Scholar
  45. Diepstra A, van Imhoff GW, Karim-Kos HE, van den Berg A, te Meerman GJ, Niens M 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 25:3101–3108PubMedCrossRefGoogle Scholar
  46. Diepstra A, Poppema S, Boot M, Visser L, Nolte IM, Niens M et al (2008) HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin’s lymphoma. Tissue Antigens 71:219–226PubMedCrossRefGoogle Scholar
  47. Drake CG (2015) Combined immune checkpoint blockade. Semin Oncol 42:656–662PubMedCrossRefGoogle Scholar
  48. Dukers DF, Jaspars LH, Vos W, Oudejans JJ, Hayes D, Cillessen S et al (2000) Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin’s disease. J Pathol 190:143–149PubMedCrossRefGoogle Scholar
  49. Ellis PA, Hart DN, Colls BM, Nimmo JC, MacDonald JE, Angus HB (1992) Hodgkin’s cells express a novel pattern of adhesion molecules. Clin Exp Immunol 90:117–123PubMedPubMedCentralCrossRefGoogle Scholar
  50. Enciso-Mora V, Broderick P, Ma Y, Jarrett RF, Hjalgrim H, Hemminki K 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 42:1126–1130PubMedPubMedCentralCrossRefGoogle Scholar
  51. Falini B, Stein H, Pileri S, Canino S, Farabbi R, Martelli MF et al (1987) Expression of lymphoid-associated antigens on Hodgkin’s and Reed-Sternberg cells of Hodgkin’s disease. An immunocytochemical study on lymph node cytospins using monoclonal antibodies. Histopathology 11:1229–1242PubMedCrossRefGoogle Scholar
  52. Fanale M, Assouline S, Kuruvilla J, Solal-Céligny P, Heo DS, Verhoef G et al (2014) Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol 164:258–265PubMedCrossRefGoogle Scholar
  53. Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA et al (2011) A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood 118:5119–5125PubMedPubMedCentralCrossRefGoogle Scholar
  54. Fhu CW, Graham AM, Yap CT, Al-Salam S, Castella A, Chong SM et al (2014) Reed-Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma. Blood 124:2973–2982PubMedCrossRefGoogle Scholar
  55. Fischer M, Juremalm M, Olsson N, Backlin C, Sundström C, Nilsson K et al (2003) Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. Int J Cancer 107:197–201PubMedCrossRefGoogle Scholar
  56. Foss HD, Hummel M, Gottstein S, Ziemann K, Falini B, Herbst H et al (1995) Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin's disease. Am J Pathol 146:33–39PubMedPubMedCentralGoogle Scholar
  57. Foss HD, Herbst H, Gottstein S, Demel G, Araujo I, Stein H (1996) Interleukin-8 in Hodgkin’s disease. preferential expression by reactive cells and association with neutrophil density. Am J Pathol 148:1229–1236PubMedPubMedCentralGoogle Scholar
  58. Frampton M, da Silva Filho MI, Broderick P, Thomsen H, Försti A, Vijayakrishnan J et al (2013) Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s lymphoma. Nat Commun 4:2549PubMedPubMedCentralCrossRefGoogle Scholar
  59. Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S 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 108:2280–2289PubMedCrossRefGoogle Scholar
  60. Gerdemann U, Katari U, Christin AS, Cruz CR, Tripic T, Rousseau A et al (2011) Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma. Mol Ther 19:2258–2268PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gibcus JH, Tan LP, Harms G, Schakel RN, de Jong D, Blokzijl T et al (2009) Hodgkin lymphoma cell lines are characterized by a specific miRNA expression profile. Neoplasia 11:167–176PubMedPubMedCentralCrossRefGoogle Scholar
  62. Glimelius I, Edstrom A, Amini RM, Fischer M, Nilsson G, Sundström C et al (2006) IL-9 expression contributes to the cellular composition in Hodgkin lymphoma. Eur J Haematol 76:278–283PubMedCrossRefGoogle Scholar
  63. Glimelius I, Rubin J, Rostgaard K, Amini RM, Simonsson M, Sorensen KM et al (2011) Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin’s lymphoma—a population-based study. Eur J Haematol 87:208–216PubMedCrossRefGoogle Scholar
  64. Greaves P, Clear A, Owen A, Iqbal S, Lee A, Matthews J et al (2013) Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood 122:2856–2863PubMedPubMedCentralCrossRefGoogle Scholar
  65. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E 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 lymphoma. Blood 116:3268–3277PubMedPubMedCentralCrossRefGoogle Scholar
  66. Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ et al (2015) Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A 112:E1116–E1125PubMedPubMedCentralCrossRefGoogle Scholar
  67. Gruss HJ, Brach MA, Drexler HG, Bross KJ, Herrmann F (1992) Interleukin 9 is expressed by primary and cultured Hodgkin and Reed-Sternberg cells. Cancer Res 52:1026–1031PubMedGoogle Scholar
  68. Gruss HJ, Hirschstein D, Wright B, Ulrich D, Caligiuri MA, Barcos M et al (1994) Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin’s disease. Blood 84:2305–2314PubMedGoogle Scholar
  69. Gruss HJ, Ulrich D, Braddy S, Armitage RJ, Dower SK (1995) Recombinant CD30 ligand and CD40 ligand share common biological activities on Hodgkin and Reed-Sternberg cells. Eur J Immunol 25:2083–2089PubMedCrossRefGoogle Scholar
  70. Guidetti A, Carlo-Stella C, Locatelli SL, Malorni W, Mortarini R, Viviani S et al (2014) Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases. Clin Cancer Res 20:5641–5651PubMedCrossRefGoogle Scholar
  71. Gunawardana J, Chan FC, Telenius A, Woolcock B, Kridel R, Tan KL et al (2014) Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet 46:329–335PubMedCrossRefGoogle Scholar
  72. Han H, Xue-Franzen Y, Miao X, Nagy E, Li N, Xu D et al (2015) Early growth response gene (EGR)-1 regulates leukotriene D4-induced cytokine transcription in Hodgkin lymphoma cells. Prostaglandins Other Lipid Mediat 121:122–130PubMedCrossRefGoogle Scholar
  73. Hanamoto H, Nakayama T, Miyazato H, Takegawa S, Hieshima K, Tatsumi Y et al (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 164:997–1006PubMedPubMedCentralCrossRefGoogle Scholar
  74. Harrison SJ, Hsu AK, Neeson P, Younes A, Sureda A, Engert A et al (2014) Early thymus and activation-regulated chemokine (TARC) reduction and response following panobinostat treatment in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant. Leuk Lymphoma 55:1053–1060PubMedCrossRefGoogle Scholar
  75. Herbst H, Foss HD, Samol J, Araujo I, Klotzbach H, Krause H et al (1996a) Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin’s disease. Blood 87:2918–2929PubMedGoogle Scholar
  76. Herbst H, Raff T, Stein H (1996b) Phenotypic modulation of Hodgkin and Reed-Sternberg cells by Epstein-Barr virus. J Pathol 179:54–59PubMedCrossRefGoogle Scholar
  77. Herbst H, Samol J, Foss HD, Raff T, Niedobitek G (1997) Modulation of interleukin-6 expression in Hodgkin and Reed-Sternberg cells by Epstein-Barr virus. J Pathol 182:299–306PubMedCrossRefGoogle Scholar
  78. Heuser C, Diehl V, Abken H, Hombach A (2003) Anti-CD30-IL-12 antibody-cytokine fusion protein that induces IFN-gamma secretion of T cells and NK cell-mediated lysis of Hodgkin’s lymphoma-derived tumor cells. Int J Cancer 106:545–552PubMedCrossRefGoogle Scholar
  79. Hinz M, Loser P, Mathas S, Krappmann D, Dorken B, Scheidereit C (2001) Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 97:2798–2807PubMedCrossRefGoogle Scholar
  80. Hinz M, Lemke P, Anagnostopoulos I, Hacker C, Krappmann D, Mathas S 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 196:605–617PubMedPubMedCentralCrossRefGoogle Scholar
  81. Hjalgrim H, Rostgaard K, Johnson PC, Lake A, Shield L, Little AM et al (2010) HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci U S A 107:6400–6405PubMedPubMedCentralCrossRefGoogle Scholar
  82. Ho WT, Pang WL, Chong SM, Castella A, Al-Salam S, Tan TE et al (2013) Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression. Cancer Res 73:652–661PubMedCrossRefGoogle Scholar
  83. Holz MS, Janning A, Renne C, Gattenlohner S, Spieker T, Brauninger A (2013) Induction of endoplasmic reticulum stress by sorafenib and activation of NF-kappaB by lestaurtinib as a novel resistance mechanism in Hodgkin lymphoma cell lines. Mol Cancer Ther 12:173–183PubMedCrossRefGoogle Scholar
  84. Hombach A, Heuser C, Abken H (2005) Simultaneous targeting of IL2 and IL12 to Hodgkin's lymphoma cells enhances activation of resting NK cells and tumor cell lysis. Int J Cancer 115:241–247PubMedCrossRefGoogle Scholar
  85. Horie R, Watanabe T, Morishita Y, Ito K, Ishida T, Kanegae Y et al (2002) Ligand-independent signaling by overexpressed CD30 drives NF-kappaB activation in Hodgkin-Reed-Sternberg cells. Oncogene 21:2493–2503PubMedCrossRefGoogle Scholar
  86. Huang X, Kushekhar K, Nolte I, Kooistra W, Visser L, Bouwman I et al (2012a) HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS One 7:e39986PubMedPubMedCentralCrossRefGoogle Scholar
  87. Huang X, Hepkema B, Nolte I, Kushekhar K, Jongsma T, Veenstra R et al (2012b) HLA-A*02:07 is a protective allele for EBV negative and a susceptibility allele for EBV positive classical Hodgkin lymphoma in china. PLoS One 7:e31865PubMedPubMedCentralCrossRefGoogle Scholar
  88. Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S et al (2006) Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 66:5716–5722PubMedCrossRefGoogle Scholar
  89. Jacob MC, Agrawal S, Chaperot L, Giroux C, Gressin R, Le Marc’Hadour F et al (1999) Quantification of cellular adhesion molecules on malignant B cells from non-Hodgkin’s lymphoma. Leukemia 13:1428–1433PubMedCrossRefGoogle Scholar
  90. Jacobs J, Deschoolmeester V, Zwaenepoel K, Rolfo C, Silence K, Rottey S et al (2015) CD70: an emerging target in cancer immunotherapy. Pharmacol Therap 155:1–10CrossRefGoogle Scholar
  91. Jahn T, Zuther M, Friedrichs B, Heuser C, Guhlke S, Abken H et al (2012) An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack. PLoS One 7:e44482PubMedPubMedCentralCrossRefGoogle Scholar
  92. Janik JE, Morris JC, O’Mahony D, Pittaluga S, Jaffe ES, Redon CE et al (2015) 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma. Proc Natl Acad Sci U S A 112:13045–13050PubMedPubMedCentralCrossRefGoogle Scholar
  93. Jarrett RF (2002) Viruses and Hodgkin’s lymphoma. Ann Oncol 13(Suppl 1):23–29PubMedCrossRefGoogle Scholar
  94. Jona A, Khaskhely N, Buglio D, Shafer JA, Derenzini E, Bollard CM et al (2011) The histone deacetylase inhibitor entinostat (SNDX-275) induces apoptosis in Hodgkin lymphoma cells and synergizes with bcl-2 family inhibitors. Exp Hematol 39:1007–1017PubMedPubMedCentralCrossRefGoogle Scholar
  95. Jones RJ, Iempridee T, Wang X, Lee HC, Mertz JE, Kenney SC et al (2016) Lenalidomide, thalidomide, and pomalidomide reactivate the Epstein-Barr virus lytic cycle through phosphoinositide 3-kinase signaling and ikaros expression. Clin Cancer Res 22:4901–4912PubMedPubMedCentralCrossRefGoogle Scholar
  96. Jucker M, Abts H, Li W, Schindler R, Merz H, Günther A et al (1991) Expression of interleukin-6 and interleukin-6 receptor in Hodgkin’s disease. Blood 77:2413–2418PubMedGoogle Scholar
  97. Jundt F, Anagnostopoulos I, Bommert K, Emmerich F, Müller G, Foss HD et al (1999) Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 94:2065–2071PubMedGoogle Scholar
  98. Jungnickel B, Staratschek-Jox A, Brauninger A, Spieker T, Wolf J, Diehl V et al (2000) Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin’s lymphoma. J Exp Med 191:395–402PubMedPubMedCentralCrossRefGoogle Scholar
  99. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J 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 104:13134–13139PubMedPubMedCentralCrossRefGoogle Scholar
  100. Kadin M, Butmarc J, Elovic A, Wong D (1993) Eosinophils are the major source of transforming growth factor-beta 1 in nodular sclerosing Hodgkin’s disease. Am J Pathol 142:11–16PubMedPubMedCentralGoogle Scholar
  101. Kapp U, Yeh WC, Patterson B, Elia AJ, Kägi D, Ho A et al (1999) Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 189:1939–1946PubMedPubMedCentralCrossRefGoogle Scholar
  102. Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S et al (2016) Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 534:402–406PubMedCrossRefGoogle Scholar
  103. Kelley TW, Parker CJ (2010) CD4 (+)CD25 (+)Foxp3 (+) regulatory T cells and hematologic malignancies. Front Biosci 2:980–992CrossRefGoogle Scholar
  104. Khabar KS (2010) Post-transcriptional control during chronic inflammation and cancer: a focus on AU-rich elements. Cell Mol Life Sci 67:2937–2955PubMedPubMedCentralCrossRefGoogle Scholar
  105. Klein JM, Henke A, Sauer M, Bessler M, Reiners KS, Engert A et al (2013) The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines. PLoS One 8:e79502PubMedPubMedCentralCrossRefGoogle Scholar
  106. Koh YW, Jeon YK, Yoon DH, Suh C, Huh J (2016) Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma. Tumour Biol 37:7507–7514PubMedCrossRefGoogle Scholar
  107. Kube D, Holtick U, Vockerodt M, Ahmadi T, Haier B, Behrmann I et al (2001) STAT3 is constitutively activated in Hodgkin cell lines. Blood 98:762–770PubMedCrossRefGoogle Scholar
  108. Küppers R, Engert A, Hansmann ML (2012) Hodgkin lymphoma. J Clin Invest 122:3439–3447PubMedPubMedCentralCrossRefGoogle Scholar
  109. Kushekhar K, van den Berg A, Nolte I, Hepkema B, Visser L, Diepstra A (2014) Genetic associations in classical Hodgkin lymphoma: a systematic review and insights into susceptibility mechanisms. Cancer Epidemiol Biomarkers Prev 23:2737–2747PubMedCrossRefGoogle Scholar
  110. Lake A, Shield LA, Cordano P, Chui DT, Osborne J, Crae S et al (2009) Mutations of NFKBIA, encoding IkappaB alpha, are a recurrent finding in classical Hodgkin lymphoma but are not a unifying feature of non-EBV-associated cases. Int J Cancer 125:1334–1342PubMedCrossRefGoogle Scholar
  111. Lamprecht B, Kreher S, Anagnostopoulos I, Jöhrens K, Monteleone G, Jundt F 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 112:3339–3347PubMedCrossRefGoogle Scholar
  112. Lemoine M, Derenzini E, Buglio D, Medeiros LJ, Davis RE, Zhang J et al (2012) The pan-deacetylase inhibitor panobinostat induces cell death and synergizes with everolimus in Hodgkin lymphoma cell lines. Blood 119:4017–4025PubMedPubMedCentralCrossRefGoogle Scholar
  113. Lennerz JK, Hoffmann K, Bubolz AM, Lessel D, Welke C, Rüther N et al (2015) Suppressor of cytokine signaling 1 gene mutation status as a prognostic biomarker in classical Hodgkin lymphoma. Oncotarget 6:29097–29110PubMedPubMedCentralCrossRefGoogle Scholar
  114. Leucci E, Zriwil A, Gregersen LH, Jensen KT, Obad S, Bellan C et al (2012) Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Oncogene 31:5081–5089PubMedCrossRefGoogle Scholar
  115. Liu Y, Abdul Razak FR, Terpstra M, Chan FC, Saber A, Nijland M et al (2014) The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 28:2248–2251PubMedCrossRefGoogle Scholar
  116. Lui PY, Jin DY, Stevenson NJ (2015) MicroRNA: master controllers of intracellular signaling pathways. Cell Mol Life Sci 72:3531–3542PubMedCrossRefGoogle Scholar
  117. Ma Y, Visser L, Blokzijl T, Harms G, Atayar C, Poppema S et al (2008a) The CD4+CD26- T-cell population in classical Hodgkin’s lymphoma displays a distinctive regulatory T-cell profile. Lab Invest 88:482–490PubMedCrossRefGoogle Scholar
  118. Ma Y, Visser L, Roelofsen H, de Vries M, Diepstra A, van Imhoff G et al (2008b) Proteomics analysis of Hodgkin lymphoma: identification of new players in the cross-talk between HRS cells and infiltrating lymphocytes. Blood 111:2339–2346PubMedCrossRefGoogle Scholar
  119. Ma X, Becker Buscaglia LE, Barker JR, Li Y (2011) MicroRNAs in NF-kappaB signaling. J Mol Cell Biol 3:159–166PubMedPubMedCentralCrossRefGoogle Scholar
  120. Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN et al (2004) Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103:1755–1762PubMedCrossRefGoogle Scholar
  121. Marshall NA, Culligan DJ, Tighe J, Johnston PW, Barker RN, Vickers MA (2007) The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin’s lymphoma. Exp Hematol 35:596–604PubMedCrossRefGoogle Scholar
  122. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL et al (2012) PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 119:1897–1900PubMedCrossRefGoogle Scholar
  123. Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M et al (1991a) Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma. Blood 78:1311–1317PubMedGoogle Scholar
  124. Merz H, Fliedner A, Orscheschek K, Binder T, Sebald W, Müller-Hermelink HK et al (1991b) Cytokine expression in T-cell lymphomas and Hodgkin’s disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth. Am J Pathol 139:1173–1180PubMedPubMedCentralGoogle Scholar
  125. Mizuno H, Nakayama T, Miyata Y, Saito S, Nishiwaki S, Nakao N et al (2012) Mast cells promote the growth of Hodgkin’s lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib. Leukemia 26:2269–2276PubMedCrossRefGoogle Scholar
  126. Molin D, Fischer M, Xiang Z, Larsson U, Harvima I, Venge P et al (2001) Mast cells express functional CD30 ligand and are the predominant CD30L-positive cells in Hodgkin’s disease. Br J Haematol 114:616–623PubMedCrossRefGoogle Scholar
  127. Molin D, Edstrom A, Glimelius I, Glimelius B, Nilsson G, Sundström C et al (2002) Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 119:122–124PubMedCrossRefGoogle Scholar
  128. Monroy CM, Cortes AC, Lopez MS, D’Amelio AM Jr, Etzel CJ, Younes A et al (2011) Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes. Mol Carcinog 50:36–46PubMedCrossRefGoogle Scholar
  129. Morales O, Mrizak D, Francois V, Mustapha R, Miroux C, Depil S et al (2014) Epstein-Barr virus infection induces an increase of T regulatory type 1 cells in Hodgkin lymphoma patients. Br J Haematol 166:875–890PubMedCrossRefGoogle Scholar
  130. Mottok A, Renne C, Willenbrock K, Hansmann ML, Brauninger A (2007) Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood 110:3387–3390PubMedCrossRefGoogle Scholar
  131. Munro JM, Freedman AS, Aster JC, Gribben JG, Lee NC, Rhynhart KK et al (1994) In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin’s disease. Blood 83:793–798PubMedGoogle Scholar
  132. Murray PG, Constandinou CM, Crocker J, Young LS, Ambinder RF (1998) Analysis of major histocompatibility complex class I, TAP expression, and LMP2 epitope sequence in Epstein-Barr virus-positive Hodgkin’s disease. Blood 92:2477–2483PubMedGoogle Scholar
  133. Navarro A, Gaya A, Martinez A, Urbano-Ispizua A, Pons A, Balagué O et al (2008) MicroRNA expression profiling in classic Hodgkin lymphoma. Blood 111:2825–2832PubMedCrossRefGoogle Scholar
  134. 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 48:160–163PubMedPubMedCentralCrossRefGoogle Scholar
  135. Newcom SR, Kadin ME, Ansari AA, Diehl V (1988) L-428 nodular sclerosing Hodgkin’s cell secretes a unique transforming growth factor-beta active at physiologic pH. J Clin Invest 82:1915–1921PubMedPubMedCentralCrossRefGoogle Scholar
  136. Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A, Platteel M 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 110:3310–3315PubMedCrossRefGoogle Scholar
  137. Nieters A, Beckmann L, Deeg E, Becker N (2006) Gene polymorphisms in toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk. Genes Immun 7:615–624PubMedCrossRefGoogle Scholar
  138. Nomoto J, Hiramoto N, Kato M, Sanada M, Maeshima AM, Taniguchi H et al (2012) Deletion of the TNFAIP3/A20 gene detected by FICTION analysis in classical Hodgkin lymphoma. BMC Cancer 12:457PubMedPubMedCentralCrossRefGoogle Scholar
  139. Ohshima K, Akaiwa M, Umeshita R, Suzumiya J, Izuhara K, Kikuchi M (2001) Interleukin-13 and interleukin-13 receptor in Hodgkin’s disease: possible autocrine mechanism and involvement in fibrosis. Histopathology 38:368–375PubMedCrossRefGoogle Scholar
  140. Ohshima K, Tutiya T, Yamaguchi T, Suzuki K, Suzumiya J, Kawasaki C 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 98:567–572PubMedCrossRefGoogle Scholar
  141. Oki Y, Buglio D, Zhang J, Ying Y, Zhou S, Sureda A et al (2014) Immune regulatory effects of panobinostat in patients with Hodgkin lymphoma through modulation of serum cytokine levels and T-cell PD1 expression. Blood Cancer J 4:e236PubMedPubMedCentralCrossRefGoogle Scholar
  142. Otto C, Giefing M, Massow A, Vater I, Gesk S, Schlesner M et al (2012) Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphoma. Br J Haematol 157:702–708PubMedCrossRefGoogle Scholar
  143. Oudejans JJ, Jiwa NM, Kummer JA, Horstman A, Vos W, Baak JP 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 87:3844–3851PubMedGoogle Scholar
  144. Pang WL, Ho WT, Schwarz H (2013) Ectopic CD137 expression facilitates the escape of Hodgkin and Reed-Sternberg cells from immunosurveillance. Oncoimmunology 2:e23441PubMedPubMedCentralCrossRefGoogle Scholar
  145. Perna SK, De Angelis B, Pagliara D, Hasan ST, Zhang L, Mahendravada A et al (2013) Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition: Implications for adoptive T cell-based therapies for lymphoma. Clin Cancer Res 19:106–117PubMedCrossRefGoogle Scholar
  146. Pinto A, Aldinucci D, Gloghini A, Zagonel V, Degan M, Improta S et al (1996) Human eosinophils express functional CD30 ligand and stimulate proliferation of a Hodgkin's disease cell line. Blood 88:3299–3305PubMedGoogle Scholar
  147. Pinto A, Aldinucci D, Gloghini A, Zagonel V, Degan M, Perin V et al (1997) The role of eosinophils in the pathobiology of Hodgkin’s disease. Ann Oncol 8(Suppl 2):89–96PubMedCrossRefGoogle Scholar
  148. Ree HJ, Crowley JP, Leone LA (1981) Macrophage-histiocyte lysozyme activity in relation to the clinical presentation of Hodgkin’s disease. An immunohistochemical study. Cancer 47:1988–1993PubMedCrossRefGoogle Scholar
  149. Reichel J, Chadburn A, Rubinstein PG, Giulino-Roth L, Tam W, Liu Y et al (2015) Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 125:1061–1072PubMedCrossRefGoogle Scholar
  150. Reiners KS, Kessler J, Sauer M, Rothe A, Hansen HP, Reusch U et al (2013) Rescue of impaired NK cell activity in Hodgkin lymphoma with bispecific antibodies in vitro and in patients. Mol Ther 21:895–903PubMedPubMedCentralCrossRefGoogle Scholar
  151. Renne C, Willenbrock K, Küppers R, Hansmann ML, Brauninger A (2005) Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. Blood 105:4051–4059PubMedCrossRefGoogle Scholar
  152. Renner C, Jung W, Sahin U, Denfeld R, Pohl C, Trümper L et al (1994) Cure of xenografted human tumors by bispecific monoclonal antibodies and human T cells. Science 264:833–835PubMedCrossRefGoogle Scholar
  153. Renner C, Ohnesorge S, Held G, Bauer S, Jung W, Pfitzenmeier JP et al (1996) T cells from patients with Hodgkin’s disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28. Blood 88:236–241PubMedGoogle Scholar
  154. Renner C, Held G, Ohnesorge S, Bauer S, Gerlach K, Pfitzenmeier JP et al (1997) Role of perforin, granzymes and the proliferative state of the target cells in apoptosis and necrosis mediated by bispecific-antibody-activated cytotoxic T cells. Cancer Immunol Immunother 44:70–76PubMedCrossRefGoogle Scholar
  155. Riemersma SA, Oudejans JJ, Vonk MJ, Dreef EJ, Prins FA, Jansen PM et al (2005) High numbers of tumour-infiltrating activated cytotoxic T lymphocytes, and frequent loss of HLA class I and II expression, are features of aggressive B cell lymphomas of the brain and testis. J Pathol 206:328–336PubMedCrossRefGoogle Scholar
  156. Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H et al (2016) PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690–2697PubMedPubMedCentralCrossRefGoogle Scholar
  157. Salipante SJ, Adey A, Thomas A, Lee C, Liu YJ, Kumar A et al (2016) Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma. Genes Chromosomes Cancer 55:278–287PubMedCrossRefGoogle Scholar
  158. Samoszuk M, Nansen L (1990) Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin’s disease with eosinophilia. Blood 75:13–16PubMedGoogle Scholar
  159. Sanders ME, Makgoba MW, Sussman EH, Luce GE, Cossman J, Shaw S (1988) Molecular pathways of adhesion in spontaneous rosetting of T-lymphocytes to the Hodgkin’s cell line L428. Cancer Res 48:37–40PubMedGoogle Scholar
  160. Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE et al (2007) Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 110:2620–2630PubMedPubMedCentralCrossRefGoogle Scholar
  161. Scheeren FA, Diehl SA, Smit LA, Beaumont T, Naspetti M, Bende RJ et al (2008) IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 111:4706–4715PubMedPubMedCentralCrossRefGoogle Scholar
  162. Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G et al (2009) TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 206:981–989PubMedPubMedCentralCrossRefGoogle Scholar
  163. Schneider M, Schneider S, Zuhlke-Jenisch R, Klapper W, Sundström C, Hartmann S et al (2015) Alterations of the CD58 gene in classical Hodgkin lymphoma. Genes Chromosomes Cancer 54:638–645PubMedCrossRefGoogle Scholar
  164. Schoof N, von Bonin F, Trumper L, Kube D (2009) HSP90 is essential for Jak-STAT signaling in classical Hodgkin lymphoma cells. Cell Commun Signal 7:17PubMedPubMedCentralCrossRefGoogle Scholar
  165. Schreck S, Friebel D, Buettner M, Distel L, Grabenbauer G, Young LS et al (2009) Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. Hematol Oncol 27:31–39PubMedCrossRefGoogle Scholar
  166. Skinnider BF, Kapp U, Mak TW (2002a) The role of interleukin 13 in classical Hodgkin lymphoma. Leuk Lymphoma 43:1203–1210PubMedCrossRefGoogle Scholar
  167. Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U et al (2002b) Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 99:618–626PubMedCrossRefGoogle Scholar
  168. Springer TA (1990) Adhesion receptors of the immune system. Nature 346:425–434PubMedCrossRefGoogle Scholar
  169. Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: Cell adhesion receptors of the immune system. Annu Rev Immunol 5:223–252PubMedCrossRefGoogle Scholar
  170. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T et al (2010) Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 362:875–885PubMedPubMedCentralCrossRefGoogle Scholar
  171. Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P et al (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471:377–381PubMedPubMedCentralCrossRefGoogle Scholar
  172. Subbiah V, Brown RE, McGuire MF, Buryanek J, Janku F, Younes A et al (2014) A novel immunomodulatory molecularly targeted strategy for refractory Hodgkin’s lymphoma. Oncotarget 5:95–102PubMedCrossRefGoogle Scholar
  173. Sun Y, Chen JH, Fu Y (2004) Immunotherapy with agonistic anti-CD137: two sides of a coin. Cell Mol Immunol 1:31–36PubMedGoogle Scholar
  174. Tanijiri T, Shimizu T, Uehira K, Yokoi T, Amuro H, Sugimoto H 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 82:576–584PubMedCrossRefGoogle Scholar
  175. Teofili L, Di Febo AL, Pierconti F, Maggiano N, Bendandi M, Rutella S et al (2001) Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease. Blood 97:1063–1069PubMedCrossRefGoogle Scholar
  176. Terada N, Hamano N, Nomura T, Numata T, Hirai K, Nakajima T et al (2000) Interleukin-13 and tumour necrosis factor-alpha synergistically induce eotaxin production in human nasal fibroblasts. Clin Exp Allergy 30:348–355PubMedCrossRefGoogle Scholar
  177. Trieu Y, Wen XY, Skinnider BF, Bray MR, Li Z, Claudio JO et al (2004) Soluble interleukin-13Ralpha2 decoy receptor inhibits Hodgkin’s lymphoma growth in vitro and in vivo. Cancer Res 64:3271–3275PubMedCrossRefGoogle Scholar
  178. Trumper L, Jung W, Daus H, Mechtersheimer G, von Bonin F, Pfreundschuh M (2001) Assessment of clonality of rosetting T lymphocytes in Hodgkin’s disease by single-cell polymerase chain reaction: detection of clonality in a polyclonal background in a case of lymphocyte predominance Hodgkin’s disease. Ann Hematol 80:653–661PubMedCrossRefGoogle Scholar
  179. Tureci O, Schmitt H, Fadle N, Pfreundschuh M, Sahin U (1997) Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin’s disease. J Biol Chem 272:6416–6422PubMedCrossRefGoogle Scholar
  180. Twa DDW, Chan FC, Ben-Neriah S, Woolcock BW, Mottok A, Tan KL et al (2014) Genomic rearrangements involving programmed cell death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123:2062–2065PubMedCrossRefGoogle Scholar
  181. Ullrich K, Blumenthal-Barby F, Lamprecht B, Köchert K, Lenze D, Hummel M 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 29:1213–1218PubMedCrossRefGoogle Scholar
  182. Urayama KY, Jarrett RF, Hjalgrim H, Diepstra A, Kamatani Y, Chabrier A et al (2012) Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 104:240–253PubMedPubMedCentralCrossRefGoogle Scholar
  183. 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 154:1685–1691PubMedPubMedCentralCrossRefGoogle Scholar
  184. Van Roosbroeck K, Ferreiro JF, Tousseyn T, van der Krogt JA, Michaux L, Pienkowska-Grela B et al (2016) Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies. Genes Chromosomes Cancer 55:428–441PubMedCrossRefGoogle Scholar
  185. Van Vlierberghe P, De Weer A, Mestdagh P, Feys T, De Preter K, De Paepe P et al (2009) Comparison of miRNA profiles of microdissected Hodgkin/Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells reveals a distinct subset of differentially expressed miRNAs. Br J Haematol 147:686–690PubMedCrossRefGoogle Scholar
  186. Vandenberghe P, Wlodarska I, Tousseym T, Dehaspe L, Dierickx D, Verheecke M et al (2015) Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced stage Hodgkin’s lymphoma by sequencing of circulating cell-free DNA: a technical proof-of-principle study. Lancet Haematol 2:e55–e65PubMedCrossRefGoogle Scholar
  187. von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S et al (2015) An open-label, multicenter, phase I/II study of JNJ-40346527, a CSF-1R inhibitor, in patients with relapsed or refractory Hodgkin lymphoma. Clin Cancer Res 21:1843–1850CrossRefGoogle Scholar
  188. Wagner HJ, Bollard CM, Vigouroux S, Huls MH, Anderson R, Prentice HG et al (2004) A strategy for treatment of Epstein-Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells. Cancer Gene Ther 11:81–91PubMedCrossRefGoogle Scholar
  189. Warren HS, Smyth MJ (1999) NK cells and apoptosis. Immunol Cell Biol 77:64–75PubMedCrossRefGoogle Scholar
  190. Watanabe M, Nakano K, Togano T, Nakashima M, Higashihara M, Kadin ME et al (2011) Targeted repression of overexpressed CD30 downregulates NF-kappaB and ERK1/2 pathway in Hodgkin lymphoma cell lines. Oncol Res 19:463–469PubMedCrossRefGoogle Scholar
  191. Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K et al (2006) Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 25:2679–2684PubMedCrossRefGoogle Scholar
  192. 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:e417PubMedPubMedCentralCrossRefGoogle Scholar
  193. Xu C, Plattel W, van den Berg A, Rüther N, Huang X, Wang M et al (2012) Expression of the c-met oncogene by tumor cells predicts a favorable outcome in classical Hodgkin's lymphoma. Haematologica 97:572–578PubMedPubMedCentralCrossRefGoogle Scholar
  194. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M et al (2008) PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111:3220–3224PubMedCrossRefGoogle Scholar
  195. Yang ZZ, Grote DM, Xiu B, Ziesmer SC, Price-Troska TL et al (2014) TGF-beta upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. Leukemia 28:1872–1884PubMedPubMedCentralCrossRefGoogle Scholar
  196. Yoshie O, Matshushima K (2014) CCR4 and its ligands: from bench to bedside. Int Immunol 27:11–20PubMedCrossRefGoogle Scholar
  197. Younes A, Romaguera J, Hagemeister F, McLaughlin P, Rodriguez MA, Fiumara P et al (2003) A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer 98:310–314PubMedCrossRefGoogle Scholar
  198. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. New Engl J Med 363:1812–1821PubMedCrossRefGoogle Scholar
  199. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ et al (2005) The tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6(12):1245–1252PubMedCrossRefGoogle Scholar
  200. Zocchi MR, Catellani S, Canevali P, Tavella S, Garuti A, Villaggio B et al (2012) High ERp5/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas. Blood 119:1479–1489PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pathology and Medical BiologyUniversity of Groningen, University Medical Center GroningenGZ GroningenThe Netherlands
  2. 2.Center for Lymphoid Cancer, British Columbia Cancer AgencyVancouverCanada
  3. 3.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada

Personalised recommendations