{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:55:06Z","timestamp":1792086906230,"version":"4.4.0"},"reference-count":176,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T00:00:00Z","timestamp":1557878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 15844"],"award-info":[{"award-number":["IG 15844"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed\u2013Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and \u201ceducate\u201d (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.<\/jats:p>","DOI":"10.3390\/ijms20102416","type":"journal-article","created":{"date-parts":[[2019,5,15]],"date-time":"2019-05-15T11:37:40Z","timestamp":1557920260000},"page":"2416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Formation of the Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4548-3566","authenticated-orcid":false,"given":"Donatella","family":"Aldinucci","sequence":"first","affiliation":[{"name":"Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano (PN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Borghese","sequence":"additional","affiliation":[{"name":"Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano (PN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naike","family":"Casagrande","sequence":"additional","affiliation":[{"name":"Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano (PN), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/ajh.25071","article-title":"Hodgkin lymphoma: 2018 update on diagnosis, risk-stratification, and management","volume":"93","author":"Ansell","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1182\/blood-2017-09-772632","article-title":"Biology of classical Hodgkin lymphoma: Implications for prognosis and novel therapies","volume":"131","author":"Mottok","year":"2018","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Xavier de, C.A., Maiato, H., Maia, A.F., Ribeiro, S.A., Pontes, P., Bickmore, W., Earnshaw, W.C., and Sambade, C. (2015). Reed-sternberg cells form by abscission failure in the presence of functional aurora B kinase. PLoS One., 10.","DOI":"10.1371\/journal.pone.0124629"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20729","DOI":"10.1073\/pnas.1312509110","article-title":"Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells","volume":"110","author":"Rengstl","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1182\/blood-2017-06-781989","article-title":"Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma","volume":"130","author":"Liu","year":"2017","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/ejh.12987","article-title":"An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome","volume":"100","author":"Hollander","year":"2018","journal-title":"Eur. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4609","DOI":"10.1182\/blood-2012-05-428896","article-title":"Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma","volume":"120","author":"Tiacci","year":"2012","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3439","DOI":"10.1172\/JCI61245","article-title":"Hodgkin lymphoma","volume":"122","author":"Kuppers","year":"2012","journal-title":"J. Clin. Invest."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E4513","DOI":"10.1073\/pnas.1406985111","article-title":"Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma","volume":"111","author":"Kreher","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1046\/j.1365-2141.2002.03456.x","article-title":"Expression pattern of MUM1\/IRF4 in the spectrum of pathology of Hodgkin\u2019s disease","volume":"117","author":"Carbone","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1182\/blood-2016-01-643569","article-title":"The 2016 revision of the World Health Organization classification of lymphoid neoplasms","volume":"127","author":"Swerdlow","year":"2016","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1002\/cncr.30824","article-title":"Hodgkin lymphoma classification: Are we at a crossroads?","volume":"123","author":"Carbone","year":"2017","journal-title":"Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/ijc.29467","article-title":"Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis","volume":"137","author":"Johnson","year":"2015","journal-title":"Int. J. Cancer."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Carbone, A., and Gloghini, A. (2018). Epstein Barr Virus-Associated Hodgkin Lymphoma. Cancers (Basel), 10.","DOI":"10.3390\/cancers10060163"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.semcancer.2015.06.002","article-title":"Microenvironment and HIV-related lymphomagenesis","volume":"34","author":"Pantanowitz","year":"2015","journal-title":"Semin Cancer Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"761","DOI":"10.7150\/jca.17648","article-title":"Role of tumor microenvironment in tumorigenesis","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.canlet.2015.10.007","article-title":"Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance","volume":"380","author":"Aldinucci","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Van Dalen, F.J., van Stevendaal, M.H.M.E., Fennemann, F.L., Verdoes, M., and Ilina, O. (2018). Molecular Repolarisation of Tumour-Associated Macrophages. Molecules, 24.","DOI":"10.3390\/molecules24010009"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.canlet.2015.07.039","article-title":"Tumor microenvironment: Sanctuary of the devil","volume":"368","author":"Hui","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nrm.2017.125","article-title":"Shedding light on the cell biology of extracellular vesicles","volume":"19","author":"Van","year":"2018","journal-title":"Nat Rev Mol Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Roma-Rodrigues, C., Mendes, R., Baptista, P.V., and Fernandes, A.R. (2019). Targeting Tumor Microenvironment for Cancer Therapy. Int J Mol Sci., 20.","DOI":"10.3390\/ijms20040840"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/bjh.12759","article-title":"Current status of prognostication in classical Hodgkin lymphoma","volume":"165","author":"Venkataraman","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nrc2542","article-title":"The biology of Hodgkin\u2019s lymphoma","volume":"9","author":"Kuppers","year":"2009","journal-title":"Nat Rev Cancer."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1111\/ejh.12747","article-title":"The role of tumour-infiltrating eosinophils, mast cells and macrophages in Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma in children","volume":"97","author":"Englund","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1182\/blood-2012-04-421057","article-title":"Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: A correlative study from the E2496 Intergroup trial","volume":"120","author":"Tan","year":"2012","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1056\/NEJMoa0905680","article-title":"Tumor-associated macrophages and survival in classic Hodgkin\u2019s lymphoma","volume":"362","author":"Steidl","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"794","DOI":"10.3324\/haematol.2015.132761","article-title":"The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints","volume":"101","author":"Vardhana","year":"2016","journal-title":"Haematologica"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/ejh.12583","article-title":"Tumour-associated mast cells in classical Hodgkin\u2019s lymphoma: Correlation with histological subtype, other tumour-infiltrating inflammatory cell subsets and outcome","volume":"96","author":"Andersen","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/bjh.15703","article-title":"High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms","volume":"184","author":"Gholiha","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1080\/10428190410001683633","article-title":"Interactions between tissue fibroblasts in lymph nodes and Hodgkin\/Reed-Sternberg cells","volume":"45","author":"Aldinucci","year":"2004","journal-title":"Leuk Lymphoma."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.imlet.2014.03.001","article-title":"Mechanisms of tumor escape from immune system: Role of mesenchymal stromal cells","volume":"159","author":"Poggi","year":"2014","journal-title":"Immunol Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/leu.2016.232","article-title":"Microenvironmental interactions between endothelial and lymphoma cells: A role for the canonical WNT pathway in Hodgkin lymphoma","volume":"31","author":"Linke","year":"2017","journal-title":"Leukemia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.semcancer.2013.07.002","article-title":"The microenvironment in classical Hodgkin lymphoma: An actively shaped and essential tumor component","volume":"24","author":"Liu","year":"2014","journal-title":"Semin Cancer Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3109\/10428194.2011.605190","article-title":"The role of CD40\/CD40L and interferon regulatory factor 4 in Hodgkin lymphoma microenvironment","volume":"53","author":"Aldinucci","year":"2012","journal-title":"Leuk Lymphoma."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/modpathol.2012.217","article-title":"Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma","volume":"26","author":"Hartmann","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1182\/blood.V85.3.780.bloodjournal853780","article-title":"Expression of functional CD40 antigen on Reed-Sternberg cells and Hodgkin\u2019s disease cell lines","volume":"85","author":"Carbone","year":"1995","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/ijc.23119","article-title":"Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: Involvement of CCL5\/Rantes in tumor cell growth and microenvironmental interactions","volume":"122","author":"Aldinucci","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/S0002-9440(10)63187-2","article-title":"Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin\u2019s disease with frequent infiltration of eosinophils and\/or plasma cells","volume":"164","author":"Hanamoto","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/ijc.11370","article-title":"Expression of CCL5\/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue","volume":"107","author":"Fischer","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"564","DOI":"10.3324\/haematol.2018.196725","article-title":"CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth","volume":"104","author":"Casagrande","year":"2019","journal-title":"Haematologica"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2353\/ajpath.2008.070845","article-title":"Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin\u2019s lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells","volume":"173","author":"Baumforth","year":"2008","journal-title":"Am. J. Pathol"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0002-9440(10)65424-7","article-title":"High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltratein Hodgkin\u2019s lymphoma","volume":"154","author":"Visser","year":"1999","journal-title":"Am. J. Pathol"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1365-2141.2007.06964.x","article-title":"Serum chemokine levels in Hodgkin lymphoma patients: Highly increased levels of CCL17 and CCL22","volume":"140","author":"Niens","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1182\/blood-2008-01-134783","article-title":"Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha","volume":"112","author":"Lamprecht","year":"2008","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1006\/scbi.2000.0327","article-title":"Interaction between host T cells and Reed-Sternberg cells in Hodgkin lymphomas","volume":"10","author":"Poppema","year":"2000","journal-title":"Semin Cancer Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1080\/10428190400013712","article-title":"The role of interleukin-3 in classical Hodgkin\u2019s disease","volume":"46","author":"Aldinucci","year":"2005","journal-title":"Leuk Lymphoma."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/annonc\/8.suppl_2.S89","article-title":"The role of eosinophils in the pathobiology of Hodgkin\u2019s disease","volume":"8","author":"Pinto","year":"1997","journal-title":"Ann. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/S0002-9440(10)64878-X","article-title":"Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells","volume":"160","author":"Aldinucci","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1182\/blood.V75.1.13.13","article-title":"Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin\u2019s disease with eosinophilia","volume":"75","author":"Samoszuk","year":"1990","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1084\/jem.189.12.1939","article-title":"Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells","volume":"189","author":"Kapp","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_51","first-page":"33","article-title":"Frequent expression of IL-7 gene transcripts in tumor cells of classical Hodgkin\u2019s disease","volume":"146","author":"Foss","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1002\/ijc.24389","article-title":"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\u2019s lymphoma","volume":"125","author":"Cattaruzza","year":"2009","journal-title":"Int. J. Cancer."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1182\/blood.V97.1.250","article-title":"Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma","volume":"97","author":"Skinnider","year":"2001","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/leu.2014.345","article-title":"The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells","volume":"29","author":"Ullrich","year":"2015","journal-title":"Leukemia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2784","DOI":"10.1182\/blood.V98.9.2784","article-title":"Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines","volume":"98","author":"Fiumara","year":"2001","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1182\/blood-2006-04-015958","article-title":"Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL","volume":"109","author":"Chiu","year":"2007","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1038\/sj.leu.2404627","article-title":"Paracrine promotion of tumor development by the TNF ligand APRIL in Hodgkin\u2019s Disease","volume":"21","author":"Schwaller","year":"2007","journal-title":"Leukemia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0344-0338(99)80027-2","article-title":"Basic fibroblast growth factor and fibrosis in Hodgkin\u2019s disease","volume":"195","author":"Ohshima","year":"1999","journal-title":"Pathol. Res. Pract."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1182\/blood-2015-07-660365","article-title":"Preclinical activity of the repurposed drug Auranofin in classical Hodgkin lymphoma","volume":"126","author":"Celegato","year":"2015","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1158\/2159-8290.CD-16-0850","article-title":"Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells","volume":"7","author":"Ruella","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/hon.2900100605","article-title":"Production of multiple cytokines by Hodgkin\u2019s disease derived cell lines","volume":"10","author":"Klein","year":"1992","journal-title":"Hematol. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e242","DOI":"10.1038\/emm.2016.64","article-title":"Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types","volume":"48","author":"Hong","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3398","DOI":"10.1182\/blood.V99.9.3398","article-title":"Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma","volume":"99","author":"Jundt","year":"2002","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1111\/j.1365-2141.1993.tb03138.x","article-title":"Lymphotoxin, tumour necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin\u2019s disease cases","volume":"84","author":"Foss","year":"1993","journal-title":"Br. J. Haematol."},{"key":"ref_65","first-page":"735","article-title":"Production of tumor necrosis factor-alpha and lymphotoxin by cells of Hodgkin\u2019s neoplastic cell lines HDLM-1 and KM-H2","volume":"135","author":"Hsu","year":"1989","journal-title":"Am. J. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1182\/blood-2014-05-576140","article-title":"Reed-Sternberg cell-derived lymphotoxin-alpha activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma","volume":"124","author":"Fhu","year":"2014","journal-title":"Blood"},{"key":"ref_67","first-page":"126","article-title":"Immunohistochemical detection of cells positive for colony-stimulating factor 1 in lymph nodes from reactive lymphadenitis, and Hodgkin\u2019s disease","volume":"6","author":"Moreau","year":"1992","journal-title":"Leukemia."},{"key":"ref_68","first-page":"2049","article-title":"Expression of the macrophage growth factor, CSF-1 and its receptor c-fms by a Hodgkin\u2019s disease-derived cell line and its variants","volume":"50","author":"Paietta","year":"1990","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tudor, C.S., Bruns, H., Daniel, C., Distel, L.V., Hartmann, A., Gerbitz, A., and Buettner, M.J. (2014). Macrophages and dendritic cells as actors in the immune reaction of classical Hodgkin lymphoma. PLoS One., 9.","DOI":"10.1371\/journal.pone.0114345"},{"key":"ref_70","first-page":"1209","article-title":"Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin\u2019s disease","volume":"136","author":"Kadin","year":"1990","journal-title":"Am. J. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0046-8177(93)90034-E","article-title":"Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin\u2019s Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin\u2019s disease","volume":"24","author":"Hsu","year":"1993","journal-title":"Hum. Pathol."},{"key":"ref_72","first-page":"11","article-title":"Eosinophils are the major source of transforming growth factor-beta 1 in nodular sclerosing Hodgkin\u2019s disease","volume":"142","author":"Kadin","year":"1993","journal-title":"Am. J. Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1182\/blood-2002-01-0099","article-title":"The role of cytokines in classical Hodgkin lymphoma","volume":"99","author":"Skinnider","year":"2002","journal-title":"Blood."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1182\/blood.V94.6.2065","article-title":"Hodgkin\/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils","volume":"94","author":"Jundt","year":"1999","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/path.1151","article-title":"Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin-Reed-Sternberg cells in Hodgkin\u2019s disease","volume":"197","author":"Talks","year":"2002","journal-title":"J. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.leukres.2014.05.023","article-title":"Insights in Hodgkin Lymphoma angiogenesis","volume":"38","author":"Marinaccio","year":"2014","journal-title":"Leuk. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1182\/blood.V97.6.1543","article-title":"CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease","volume":"97","author":"Buri","year":"2001","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/annonc\/13.S1.52","article-title":"Chemokines, cytokines and their receptors in Hodgkin\u2019s lymphoma cell lines and tissues","volume":"13","author":"Maggio","year":"2002","journal-title":"Ann. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1182\/blood-2011-10-386763","article-title":"PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma","volume":"119","author":"Meadows","year":"2012","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1182\/blood.V93.8.2463","article-title":"Differential chemokine expression in tissues involved by Hodgkin\u2019s disease: Direct correlation of eotaxin expression and tissue eosinophilia","volume":"93","author":"Jaffe","year":"1999","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1182\/blood-2008-01-133769","article-title":"Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines","volume":"112","author":"Buglio","year":"2008","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1097\/00000478-200107000-00011","article-title":"TARC, a CC chemokine, is frequently expressed in classic Hodgkin\u2019s lymphoma but not in NLP Hodgkin\u2019s lymphoma, T-cell-rich B-cell lymphoma, and most cases of anaplastic large cell lymphoma","volume":"25","author":"Peh","year":"2001","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1038\/modpathol.3880473","article-title":"Macrophage-derived chemokine expression in classical Hodgkin\u2019s lymphoma: Application of tissue microarrays","volume":"14","author":"Hedvat","year":"2001","journal-title":"Mod. Pathol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6392","DOI":"10.1182\/blood-2009-03-209650","article-title":"T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model","volume":"113","author":"Di","year":"2009","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1111\/j.1365-2141.2009.07945.x","article-title":"IRF4 is modulated by CD40L and by apoptotic and anti-proliferative signals in Hodgkin lymphoma","volume":"148","author":"Aldinucci","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1182\/blood-2003-07-2254","article-title":"Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells","volume":"103","author":"Jundt","year":"2004","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e1160188","DOI":"10.1080\/2162402X.2016.1160188","article-title":"CD137 signaling in Hodgkin and Reed-Sternberg cell lines induces IL-13 secretion, immune deviation and enhanced growth","volume":"5","author":"Rajendran","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1182\/blood-2013-04-499004","article-title":"The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1","volume":"122","author":"Cader","year":"2013","journal-title":"Blood"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1200\/JCO.2010.32.8401","article-title":"Molecular pathogenesis of Hodgkin\u2019s lymphoma: Increasing evidence of the importance of the microenvironment","volume":"29","author":"Steidl","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1038\/sj.leu.2403992","article-title":"Angiogenesis and mast cells in Hodgkin lymphoma","volume":"19","author":"Glimelius","year":"2005","journal-title":"Leukemia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1182\/blood-2018-04-843714","article-title":"Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment","volume":"132","author":"Cader","year":"2018","journal-title":"Blood"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1097\/MOH.0000000000000158","article-title":"Targeting immune checkpoints in lymphoma","volume":"22","author":"Ansell","year":"2015","journal-title":"Curr. Opin. Hematol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1053\/j.seminhematol.2016.05.011","article-title":"Novel agents in the treatment of Hodgkin lymphoma: Biological basis and clinical results","volume":"53","author":"Younes","year":"2016","journal-title":"Semin Hematol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.1200\/JCO.2016.67.3467","article-title":"Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure","volume":"34","author":"Armand","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed\/Refractory Classic Hodgkin Lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1200\/JCO.2017.77.3994","article-title":"Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma","volume":"36","author":"Roemer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Koh, Y.W., Park, C.S., Yoon, D.H., Suh, C., and Huh, J. (2014). CD163 expression was associated with angiogenesis and shortened survival in patients with uniformly treated classical Hodgkin lymphoma. PLoS One, 9.","DOI":"10.1371\/journal.pone.0087066"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Crane, G.M., Samols, M.A., Morsberger, L.A., Yonescu, R., Thiess, M.L., Batista, D.A., Ning, Y., Burns, K.H., Vuica-Ross, M., and Borowitz, M.J. (2016). Tumor-Infiltrating Macrophages in Post-Transplant, Relapsed Classical Hodgkin Lymphoma Are Donor-Derived. PLoS One, 11.","DOI":"10.1371\/journal.pone.0163559"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/hon.2295","article-title":"Independent prognostic impact of tumour-infiltrating macrophages in early-stage Hodgkin\u2019s lymphoma","volume":"35","author":"Gotti","year":"2017","journal-title":"Hematol Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1182\/blood-2017-03-770719","article-title":"Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma","volume":"130","author":"Carey","year":"2017","journal-title":"Blood"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1182\/blood-2017-07-796342","article-title":"Immune evasion via PD-1\/PD-L1 on NK cells and monocyte\/macrophages is more prominent in Hodgkin lymphoma than DLBCL","volume":"131","author":"Vari","year":"2018","journal-title":"Blood"},{"key":"ref_102","first-page":"756353","article-title":"Role of immune escape mechanisms in Hodgkin\u2019s lymphoma development and progression: A whole new world with therapeutic implications","volume":"2012","author":"Lejeune","year":"2012","journal-title":"Clin. Dev. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e2014039","DOI":"10.4084\/mjhid.2014.039","article-title":"Immunological deregulation in classic hodgkin lymphoma","volume":"6","author":"Romano","year":"2014","journal-title":"Mediterr. J. Hematol Infect. Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"13134","DOI":"10.1073\/pnas.0706017104","article-title":"The AP1-dependent secretion of galectin-1 by Reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma","volume":"104","author":"Juszczynski","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1182\/blood.V99.1.258","article-title":"Tissue inhibitor of metalloproteinases 1 is an autocrine and paracrine survival factor, with additional immune-regulatory functions, expressed by Hodgkin\/Reed-Sternberg cells","volume":"99","author":"Oelmann","year":"2002","journal-title":"Blood"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1158\/0008-5472.CAN-05-3252","article-title":"Prostaglandin E2 impairs CD4+ T cell activation by inhibition of lck: implications in Hodgkin\u2019s lymphoma","volume":"66","author":"Chemnitz","year":"2006","journal-title":"Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1158\/2326-6066.CIR-17-0325","article-title":"Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma","volume":"5","author":"Wein","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1084\/jem.20031080","article-title":"c-FLIP mediates resistance of Hodgkin\/Reed-Sternberg cells to death receptor-induced apoptosis","volume":"199","author":"Mathas","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Poppema, S. (2005). Immunobiology and pathophysiology of Hodgkin lymphomas. Hematology Am. Soc. Hematol Educ. Program., 231\u2013238.","DOI":"10.1182\/asheducation-2005.1.231"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1182\/blood-2011-07-370841","article-title":"High ERp5\/ADAM10 expression in lymph node microenvironment and impaired NKG2D ligands recognition in Hodgkin lymphomas","volume":"119","author":"Zocchi","year":"2012","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.4081\/ejh.2016.2606","article-title":"HLA-G expression and role in advanced-stage classical Hodgkin lymphoma","volume":"60","author":"Caocci","year":"2016","journal-title":"Eur. J. Histochem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1158\/0008-5472.CAN-12-3849","article-title":"Expression of CD137 on Hodgkin and Reed-Sternberg cells inhibits T-cell activation by eliminating CD137 ligand expression","volume":"73","author":"Ho","year":"2013","journal-title":"Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3389\/fimmu.2017.00760","article-title":"NK Cell Exhaustion","volume":"8","author":"Bi","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1182\/blood-2007-05-085159","article-title":"PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma","volume":"111","author":"Yamamoto","year":"2008","journal-title":"Blood"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.it.2016.01.002","article-title":"IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance","volume":"37","author":"Munn","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/cas.13432","article-title":"Clinical significance of tryptophan catabolism in Hodgkin lymphoma","volume":"109","author":"Masaki","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1186\/1471-2407-14-335","article-title":"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","volume":"14","author":"Choe","year":"2014","journal-title":"BMC Cancer."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1111\/ajt.13801","article-title":"Unlocking the Potential of Purinergic Signaling in Transplantation","volume":"16","author":"Zeiser","year":"2016","journal-title":"Am. J. Transplant."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/labinvest.2008.24","article-title":"The CD4+CD26- T-cell population in classical Hodgkin\u2019s lymphoma displays a distinctive regulatory T-cell profile","volume":"88","author":"Ma","year":"2008","journal-title":"Lab. Invest."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-associated macrophages as treatment targets in oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nrclinonc.2017.128","article-title":"Chimeric antigen receptor T-cell therapies for lymphoma","volume":"15","author":"Brudno","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1158\/1078-0432.CCR-18-1133","article-title":"Targeting cancer cells and tumor microenvironment in preclinical and clinical models of Hodgkin lymphoma using the dual PI3Kdelta\/gamma inhibitor RP6530","volume":"25","author":"Locatelli","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1016\/j.febslet.2014.04.011","article-title":"Pyruvate kinase M2 and cancer: An updated assessment","volume":"588","author":"Iqbal","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1158\/0008-5472.CAN-18-1351","article-title":"Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy","volume":"78","author":"Munn","year":"2018","journal-title":"Cancer Res."},{"key":"ref_126","first-page":"81","article-title":"Tumor-infiltrating regulatory T cells: Origins and features","volume":"7","author":"Deng","year":"2018","journal-title":"Am. J. Clin. Exp. Immunol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1182\/blood-2009-10-247809","article-title":"Chemokine receptors as therapeutic tools in Hodgkin lymphoma: CCR4 and beyond","volume":"115","author":"Aldinucci","year":"2010","journal-title":"Blood"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1189\/jlb.0906565","article-title":"Hodgkin\u2019s 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","volume":"82","author":"Tanijiri","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"LeBleu, V.S., and Kalluri, R. (2018). A peek into cancer-associated fibroblasts: Origins, functions and translational impact. Dis Model. Mech., 11.","DOI":"10.1242\/dmm.029447"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"4331","DOI":"10.1158\/0008-5472.CAN-08-0943","article-title":"Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells","volume":"68","author":"Mishra","year":"2008","journal-title":"Cancer Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1158\/0008-5472.CAN-08-3562","article-title":"Mesenchymal stem cells: Flip side of the coin","volume":"69","author":"Mishra","year":"2009","journal-title":"Cancer Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2741\/4207","article-title":"Stress immunity in lymphomas: Mesenchymal cells as a target of therapy","volume":"19","author":"Poggi","year":"2014","journal-title":"Front. Biosci (Landmark Ed.)"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Navarro-Tableros, V., Gomez, Y., Camussi, G., and Brizzi, M.F. (2018). Extracellular Vesicles: New Players in Lymphomas. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010041"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/path.4306","article-title":"Protrusion-guided extracellular vesicles mediate CD30 trans-signalling in the microenvironment of Hodgkin\u2019s lymphoma","volume":"232","author":"Hansen","year":"2014","journal-title":"J. Pathol."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"David, J.M., Dominguez, C., Hamilton, D.H., and Palena, C. (2016). The IL-8\/IL-8R Axis: A Double Agent in Tumor Immune Resistance. Vaccines (Basel), 4.","DOI":"10.3390\/vaccines4030022"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.3389\/fimmu.2018.01358","article-title":"Hodgkin Lymphoma-Derived Extracellular Vesicles Change the Secretome of Fibroblasts Toward a CAF Phenotype","volume":"9","author":"Dorsam","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e1421889","DOI":"10.1080\/2162402X.2017.1421889","article-title":"Specific ADAM10 inhibitors localize in exosome-like vesicles released by Hodgkin lymphoma and stromal cells and prevent sheddase activity carried to bystander cells","volume":"7","author":"Tosetti","year":"2018","journal-title":"Oncoimmunology."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1182\/blood-2014-06-537514","article-title":"Brentuximab vedotin","volume":"124","author":"Ansell","year":"2014","journal-title":"Blood"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/path.2711","article-title":"The classical Hodgkin\u2019s lymphoma microenvironment and its role in promoting tumour growth and immune escape","volume":"221","author":"Aldinucci","year":"2010","journal-title":"J. Pathol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00280-015-2918-1","article-title":"Unique features of trabectedin mechanism of action","volume":"77","author":"Larsen","year":"2016","journal-title":"Cancer Chemother Pharmacol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/bjh.15658","article-title":"The translational science of hodgkin lymphoma","volume":"184","author":"Cirillo","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrclinonc.2016.168","article-title":"PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas","volume":"14","author":"Goodman","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1182\/blood-2013-06-508044","article-title":"Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells","volume":"122","author":"Greaves","year":"2013","journal-title":"Blood"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/bjh.15695","article-title":"Novel therapeutic agents for relapsed classical Hodgkin lymphoma","volume":"184","author":"Von","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Pericart, S., Tosolini, M., Gravelle, P., Rossi, C., Traverse-Glehen, A., Amara, N., Franchet, C., Martin, E., Bezombes, C., and Laurent, G. (2018). Profiling Immune Escape in Hodgkin\u2019s and Diffuse large B-Cell Lymphomas Using the Transcriptome and Immunostaining. Cancers (Basel), 10.","DOI":"10.3390\/cancers10110415"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/imr.12519","article-title":"LAG3 (CD223) as a cancer immunotherapy target","volume":"276","author":"Andrews","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/s41598-017-18433-4","article-title":"IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential","volume":"8","author":"Boulakirba","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1182\/blood-2012-06-439570","article-title":"Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma","volume":"120","author":"Steidl","year":"2012","journal-title":"Blood"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1158\/1078-0432.CCR-14-1845","article-title":"An Open-Label, Multicenter, Phase I\/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma","volume":"21","author":"Von","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1182\/blood.V120.21.1638.1638","article-title":"CSF1R Inhibition by PLX3397 in Patients with Relapsed or Refractory Hodgkin Lymphoma: Results From a Phase 2 Single Agent Clinical Tria","volume":"120","author":"Moskowitz","year":"2012","journal-title":"Blood"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"4024","DOI":"10.1182\/blood-2014-12-614636","article-title":"A phase 1 study of the bispecific anti-CD30\/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma","volume":"125","author":"Rothe","year":"2015","journal-title":"Blood."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"6795","DOI":"10.1158\/0008-5472.CAN-17-2285","article-title":"Discovery of IDO1 Inhibitors: From Bench to Bedside","volume":"77","author":"Prendergast","year":"2017","journal-title":"Cancer Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41568-019-0106-z","article-title":"Immune control by amino acid catabolism during tumorigenesis and therapy","volume":"19","author":"Lemos","year":"2019","journal-title":"Nat. Rev. Cancer."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s11523-017-0547-9","article-title":"Modulating Tumor Immunology by Inhibiting Indoleamine 2,3-Dioxygenase (IDO): Recent Developments and First Clinical Experiences","volume":"13","author":"Davar","year":"2018","journal-title":"Target. Oncol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1365-2125.2008.03130.x","article-title":"Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers","volume":"65","author":"Abel","year":"2008","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"482","DOI":"10.2174\/157016210793499295","article-title":"Long-term immunovirogical effect and tolerability of a maraviroc-containing regimen in routine clinical practice","volume":"8","author":"Genebat","year":"2010","journal-title":"Curr. HIV Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1158\/0008-5472.CAN-11-3439","article-title":"Repurposing approved and abandoned drugs for the treatment and prevention of cancer through public-private partnership","volume":"72","author":"Weir","year":"2012","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1158\/0008-5472.CAN-11-3917","article-title":"CCR5 antagonist blocks metastasis of basal breast cancer cells","volume":"72","author":"Jiao","year":"2012","journal-title":"Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"e1150398","DOI":"10.1080\/2162402X.2016.1150398","article-title":"Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs","volume":"5","author":"Halvorsen","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"48335","DOI":"10.18632\/oncotarget.10227","article-title":"Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation","volume":"7","author":"Tanabe","year":"2016","journal-title":"Oncotarget"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ccell.2016.03.005","article-title":"Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients","volume":"29","author":"Halama","year":"2016","journal-title":"Cancer Cell."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1182\/blood-2016-12-757740","article-title":"Idelalisib is effective in patients with high-risk follicular lymphoma and early relapse after initial chemoimmunotherapy","volume":"129","author":"Gopal","year":"2017","journal-title":"Blood"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1172\/JCI99386","article-title":"PI3K p110delta inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression","volume":"129","author":"Dong","year":"2019","journal-title":"J. Clin. Invest."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nature20554","article-title":"Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells","volume":"539","author":"De","year":"2016","journal-title":"Nature"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1038\/leu.2016.224","article-title":"The novel PI3K-delta inhibitor TGR-1202 enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest","volume":"30","author":"Locatelli","year":"2016","journal-title":"Leukemia"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/annonc\/mdx028","article-title":"Phase II study of idelalisib, a selective inhibitor of PI3Kdelta, for relapsed\/refractory classical Hodgkin lymphoma","volume":"28","author":"Gopal","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s40259-017-0247-0","article-title":"Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf","volume":"31","author":"Ruella","year":"2017","journal-title":"BioDrugs"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/cyto.b.20561","article-title":"Flow cytometric analysis of CD123 is useful for immunophenotyping classical Hodgkin lymphoma","volume":"80","author":"Fromm","year":"2011","journal-title":"Cytometry B Clin. Cytom."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/tpj.2016.76","article-title":"A systems biology approach to investigate the mechanism of action of trabectedin in a model of myelomonocytic leukemia","volume":"18","author":"Mannarino","year":"2016","journal-title":"Pharmacogenom. J."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/bjc.2016.424","article-title":"Antitumour activity of trabectedin in myelodysplastic\/myeloproliferative neoplasms","volume":"116","author":"Romano","year":"2017","journal-title":"Br. J. Cancer."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1111\/bjh.15212","article-title":"Trabectedin is a novel chemotherapy agent for diffuse large B cell lymphoma","volume":"184","author":"Spriano","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/1061186X.2014.950668","article-title":"The critical role of bisphosphonates to target bone cancer metastasis: An overview","volume":"23","author":"Singh","year":"2015","journal-title":"J. Drug Target."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/annonc\/mdr159","article-title":"Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: Implications for adjuvant therapy of breast cancer","volume":"23","author":"Gallo","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"42926","DOI":"10.18632\/oncotarget.17216","article-title":"Self-assembling nanoparticles encapsulating zoledronic acid inhibit mesenchymal stromal cells differentiation, migration and secretion of proangiogenic factors and their interactions with prostate cancer cells","volume":"8","author":"Borghese","year":"2017","journal-title":"Oncotarget"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"118","DOI":"10.18632\/oncotarget.9497","article-title":"Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts","volume":"8","author":"Comito","year":"2017","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2416\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:52:16Z","timestamp":1760187136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/10\/2416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,15]]},"references-count":176,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20102416"],"URL":"https:\/\/doi.org\/10.3390\/ijms20102416","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201904.0209.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,15]]}}}