Cellular and Molecular Life Sciences

, Volume 73, Issue 8, pp 1569–1589 | Cite as

Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies

  • Camille Guillerey
  • Kyohei Nakamura
  • Slavica Vuckovic
  • Geoffrey R. Hill
  • Mark J. SmythEmail author


Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.


Multiple myeloma Tumor microenvironment Immune responses Immune escape Immunotherapy 



Antibody-dependent cellular cytotoxicity


Antigen presenting cell


A proliferation-inducing ligand


B-cell activating factor


Bone marrow


BM stromal cell


Cell-adhesion mediated drug resistance


Chimeric antigen receptor


Damage-associated molecular patterns


Dendritic cell


Graft versus host disease








Innate lymphoid cell


Killer cell immunoglobulin-like receptor




Monoclonal antibody


Myeloid-derived suppressor cells


Monoclonal gammopathy of undetermined significance


Major histocompatibility complex


Multiple myeloma


Mesenchymal stem cell


Natural killer


Pathogen-associated molecular patterns


Plasmacytoid DC


Peripheral blood mononuclear cells


Receptor activator of NF-κB


Severe combined immunodeficient


Tumor-associated macrophages


T cell receptor


Transforming growth factor


Toll-like receptor


TNF-related apoptosis inducing ligand


Regulatory T cell


Vascular endothelial growth factor



K.N. is supported by The Naito Foundation. M. J. S. is supported by a NH&MRC Australia Fellowship (628623) and Program Grant (1013667). C.G. is supported by a NH&MRC early career fellowship (1107417).


  1. 1.
    Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364(11):1046–1060. doi: 10.1056/NEJMra1011442 PubMedCrossRefGoogle Scholar
  2. 2.
    Vincent Rajkumar S (2014) Multiple myeloma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 89(10):999–1009. doi: 10.1002/ajh.23810 PubMedGoogle Scholar
  3. 3.
    International Myeloma Working G (2003) Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 121(5):749–757CrossRefGoogle Scholar
  4. 4.
    Rollig C, Knop S, Bornhauser M (2015) Multiple myeloma. Lancet 385(9983):2197–2208. doi: 10.1016/S0140-6736(14)60493-1 PubMedCrossRefGoogle Scholar
  5. 5.
    Tangye SG (2011) Staying alive: regulation of plasma cell survival. Trends Immunol 32(12):595–602. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  6. 6.
    Chu VT, Berek C (2013) The establishment of the plasma cell survival niche in the bone marrow. Immunol Rev 251(1):177–188. doi: 10.1111/imr.12011 PubMedCrossRefGoogle Scholar
  7. 7.
    Kuehl WM, Bergsagel PL (2002) Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2(3):175–187. doi: 10.1038/nrc746 PubMedCrossRefGoogle Scholar
  8. 8.
    De Raeve HR, Vanderkerken K (2005) The role of the bone marrow microenvironment in multiple myeloma. Histol Histopathol 20(4):1227–1250PubMedGoogle Scholar
  9. 9.
    Bergsagel PL, Kuehl WM (2001) Chromosome translocations in multiple myeloma. Oncogene 20(40):5611–5622. doi: 10.1038/sj.onc.1204641 PubMedCrossRefGoogle Scholar
  10. 10.
    Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O’Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WH, Munshi NC, Morgan GJ, Anderson KC (2003) Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood 102(13):4504–4511. doi: 10.1182/blood-2003-01-0016 PubMedCrossRefGoogle Scholar
  11. 11.
    Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6(2):93–106. doi: 10.1038/nri1779 PubMedCrossRefGoogle Scholar
  12. 12.
    Romano A, Conticello C, Cavalli M, Vetro C, La Fauci A, Parrinello NL, Di Raimondo F (2014) Immunological dysregulation in multiple myeloma microenvironment. BioMed Res Int 2014:198539. doi: 10.1155/2014/198539 PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kawano Y, Moschetta M, Manier S, Glavey S, Gorgun GT, Roccaro AM, Anderson KC, Ghobrial IM (2015) Targeting the bone marrow microenvironment in multiple myeloma. Immunol Rev 263(1):160–172. doi: 10.1111/imr.12233 PubMedCrossRefGoogle Scholar
  14. 14.
    De Kleer I, Willems F, Lambrecht B, Goriely S (2014) Ontogeny of myeloid cells. Front Immunol 5:423. doi: 10.3389/fimmu.2014.00423 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Matthes T, Manfroi B, Zeller A, Dunand-Sauthier I, Bogen B, Huard B (2015) Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow. Leukemia 29(9):1882–1890. doi: 10.1038/leu.2015.145 PubMedCrossRefGoogle Scholar
  16. 16.
    Zheng Y, Cai Z, Wang S, Zhang X, Qian J, Hong S, Li H, Wang M, Yang J, Yi Q (2009) Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114(17):3625–3628. doi: 10.1182/blood-2009-05-220285 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Kim J, Denu RA, Dollar BA, Escalante LE, Kuether JP, Callander NS, Asimakopoulos F, Hematti P (2012) Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells. Br J Haematol 158(3):336–346. doi: 10.1111/j.1365-2141.2012.09154.x PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Villadangos JA, Schnorrer P (2007) Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 7(7):543–555. doi: 10.1038/nri2103 PubMedCrossRefGoogle Scholar
  19. 19.
    Shortman K, Sathe P, Vremec D, Naik S, O’Keeffe M (2013) Plasmacytoid dendritic cell development. Adv Immunol 120:105–126. doi: 10.1016/B978-0-12-417028-5.00004-1 PubMedCrossRefGoogle Scholar
  20. 20.
    Cavanagh LL, Bonasio R, Mazo IB, Halin C, Cheng G, van der Velden AW, Cariappa A, Chase C, Russell P, Starnbach MN, Koni PA, Pillai S, Weninger W, von Andrian UH (2005) Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells. Nat Immunol 6(10):1029–1037. doi: 10.1038/ni1249 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Karle H, Hansen NE, Plesner T (1976) Neutrophil defect in multiple myeloma. Studies on intraneutrophilic lysozyme in multiple myeloma and malignant lymphoma. Scand J Haematol 17(1):62–70PubMedCrossRefGoogle Scholar
  22. 22.
    Wong TW, Kita H, Hanson CA, Walters DK, Arendt BK, Jelinek DF (2013) Induction of malignant plasma cell proliferation by eosinophils. PLoS One 8(7):e70554. doi: 10.1371/journal.pone.0070554 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wong D, Winter O, Hartig C, Siebels S, Szyska M, Tiburzy B, Meng L, Kulkarni U, Fahnrich A, Bommert K, Bargou R, Berek C, Chu VT, Bogen B, Jundt F, Manz RA (2014) Eosinophils and megakaryocytes support the early growth of murine MOPC315 myeloma cells in their bone marrow niches. PLoS One 9(10):e109018. doi: 10.1371/journal.pone.0109018 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Klose CS, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, Fabiunke C, Pfeifer D, Sexl V, Fonseca-Pereira D, Domingues RG, Veiga-Fernandes H, Arnold SJ, Busslinger M, Dunay IR, Tanriver Y, Diefenbach A (2014) Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157(2):340–356. doi: 10.1016/j.cell.2014.03.030 PubMedCrossRefGoogle Scholar
  25. 25.
    Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F (2012) Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37(3):463–474. doi: 10.1016/j.immuni.2012.06.012 PubMedCrossRefGoogle Scholar
  26. 26.
    Fathman JW, Bhattacharya D, Inlay MA, Seita J, Karsunky H, Weissman IL (2011) Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118(20):5439–5447. doi: 10.1182/blood-2011-04-348912 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Guillerey C, Smyth MJ (2015) NK cells and cancer immunoediting. Curr Top Microbiol Immunol. doi: 10.1007/82_2015_446 Google Scholar
  28. 28.
    Godfrey J, Benson DM Jr (2012) The role of natural killer cells in immunity against multiple myeloma. Leuk Lymphoma 53(9):1666–1676. doi: 10.3109/10428194.2012.676175 PubMedCrossRefGoogle Scholar
  29. 29.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907. doi: 10.1038/nature06309 PubMedCrossRefGoogle Scholar
  30. 30.
    Hughes V (2011) Microenvironment: neighbourhood watch. Nature 480(7377):S48–S49. doi: 10.1038/480S48a PubMedCrossRefGoogle Scholar
  31. 31.
    Di Rosa F, Pabst R (2005) The bone marrow: a nest for migratory memory T cells. Trends Immunol 26(7):360–366. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  32. 32.
    Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y, Wang G, Zou W (2012) Bone marrow and the control of immunity. Cell Mol Immunol 9(1):11–19. doi: 10.1038/cmi.2011.47 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Zhu J, Paul WE (2010) Heterogeneity and plasticity of T helper cells. Cell Res 20(1):4–12. doi: 10.1038/cr.2009.138 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Whiteside TL (2012) What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol 22(4):327–334. doi: 10.1016/j.semcancer.2012.03.004 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, Wei S, David O, Curiel TJ, Zou W (2004) Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res 64(22):8451–8455. doi: 10.1158/0008-5472.CAN-04-1987 PubMedCrossRefGoogle Scholar
  36. 36.
    Blade J, Fernandez de Larrea C, Rosinol L, Cibeira MT, Jimenez R, Powles R (2011) Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol 29(28):3805–3812. doi: 10.1200/JCO.2011.34.9290 PubMedCrossRefGoogle Scholar
  37. 37.
    Katz BZ (2010) Adhesion molecules—the lifelines of multiple myeloma cells. Semin Cancer Biol 20(3):186–195. doi: 10.1016/j.semcancer.2010.04.003 PubMedCrossRefGoogle Scholar
  38. 38.
    Klein B, Zhang XG, Lu ZY, Bataille R (1995) Interleukin-6 in human multiple myeloma. Blood 85(4):863–872PubMedGoogle Scholar
  39. 39.
    Asaoku H, Kawano M, Iwato K, Tanabe O, Tanaka H, Hirano T, Kishimoto T, Kuramoto A (1988) Decrease in BSF-2/IL-6 response in advanced cases of multiple myeloma. Blood 72(2):429–432PubMedGoogle Scholar
  40. 40.
    Mitsiades CS, McMillin DW, Klippel S, Hideshima T, Chauhan D, Richardson PG, Munshi NC, Anderson KC (2007) The role of the bone marrow microenvironment in the pathophysiology of myeloma and its significance in the development of more effective therapies. Hematol/Oncol Clin N Am 21(6):1007–1034. doi: 10.1016/j.hoc.2007.08.007 CrossRefGoogle Scholar
  41. 41.
    Kishimoto T (1989) The biology of interleukin-6. Blood 74(1):1–10PubMedGoogle Scholar
  42. 42.
    Gunn WG, Conley A, Deininger L, Olson SD, Prockop DJ, Gregory CA (2006) A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells 24(4):986–991. doi: 10.1634/stemcells.2005-0220 PubMedCrossRefGoogle Scholar
  43. 43.
    Chu VT, Frohlich A, Steinhauser G, Scheel T, Roch T, Fillatreau S, Lee JJ, Lohning M, Berek C (2011) Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol 12(2):151–159. doi: 10.1038/ni.1981 PubMedCrossRefGoogle Scholar
  44. 44.
    San-Miguel J, Blade J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ (2014) Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 123(26):4136–4142. doi: 10.1182/blood-2013-12-546374 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF (2004) Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 103(2):689–694. doi: 10.1182/blood-2003-06-2043 PubMedCrossRefGoogle Scholar
  46. 46.
    Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, Moine P, Rossi JF, Klein B, Tarte K (2004) BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 103(8):3148–3157. doi: 10.1182/blood-2003-06-1984 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, Pantesco V, De Vos J, Jourdan E, Jauch A, Legouffe E, Moos M, Fiol G, Goldschmidt H, Rossi JF, Hose D, Klein B (2005) The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 106(3):1021–1030. doi: 10.1182/blood-2004-11-4512 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, Pai C, Amin S, Tai YT, Richardson PG, Ghobrial IM, Treon SP, Daley JF, Anderson KC, Kutok JL, Munshi NC (2010) Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood 115(26):5385–5392. doi: 10.1182/blood-2009-10-246660 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Barille S, Collette M, Bataille R, Amiot M (1995) Myeloma cells upregulate interleukin-6 secretion in osteoblastic cells through cell-to-cell contact but downregulate osteocalcin. Blood 86(8):3151–3159PubMedGoogle Scholar
  50. 50.
    Yaccoby S, Wezeman MJ, Zangari M, Walker R, Cottler-Fox M, Gaddy D, Ling W, Saha R, Barlogie B, Tricot G, Epstein J (2006) Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica 91(2):192–199PubMedPubMedCentralGoogle Scholar
  51. 51.
    Podar K, Chauhan D, Anderson KC (2009) Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23(1):10–24. doi: 10.1038/leu.2008.259 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Giuliani N, Colla S, Sala R, Moroni M, Lazzaretti M, La Monica S, Bonomini S, Hojden M, Sammarelli G, Barille S, Bataille R, Rizzoli V (2002) Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood 100(13):4615–4621. doi: 10.1182/blood-2002-04-1121 PubMedCrossRefGoogle Scholar
  53. 53.
    Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I (2010) A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood 116(18):3554–3563. doi: 10.1182/blood-2010-05-283895 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, Albini A, Bussolino F, Dammacco F (1999) Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 93(9):3064–3073PubMedGoogle Scholar
  55. 55.
    Giuliani N, Storti P, Bolzoni M, Palma BD, Bonomini S (2011) Angiogenesis and multiple myeloma. Cancer Microenviron 4(3):325–337. doi: 10.1007/s12307-011-0072-9 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ribatti D, Nico B, Vacca A (2015) Multiple myeloma as a model for the role of bone marrow niches in the control of angiogenesis. Int Rev Cell Molec Biol 314:259–282. doi: 10.1016/bs.ircmb.2014.10.004 CrossRefGoogle Scholar
  57. 57.
    Berardi S, Ria R, Reale A, De Luisi A, Catacchio I, Moschetta M, Vacca A (2013) Multiple myeloma macrophages: pivotal players in the tumor microenvironment. J Oncol 2013:183602. doi: 10.1155/2013/183602 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Tartour E, Pere H, Maillere B, Terme M, Merillon N, Taieb J, Sandoval F, Quintin-Colonna F, Lacerda K, Karadimou A, Badoual C, Tedgui A, Fridman WH, Oudard S (2011) Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 30(1):83–95. doi: 10.1007/s10555-011-9281-4 PubMedCrossRefGoogle Scholar
  59. 59.
    Rossi M, Botta C, Correale P, Tassone P, Tagliaferri P (2013) Immunologic microenvironment and personalized treatment in multiple myeloma. Exp Opin Biol Ther 13(Suppl 1):S83–S93. doi: 10.1517/14712598.2013.799130 CrossRefGoogle Scholar
  60. 60.
    Tete SM, Bijl M, Sahota SS, Bos NA (2014) Immune defects in the risk of infection and response to vaccination in monoclonal gammopathy of undetermined significance and multiple myeloma. Front Immunol 5:257. doi: 10.3389/fimmu.2014.00257 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Xu FH, Sharma S, Gardner A, Tu Y, Raitano A, Sawyers C, Lichtenstein A (1998) Interleukin-6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway. Blood 92(1):241–251PubMedGoogle Scholar
  62. 62.
    Zheng Y, Yang J, Qian J, Qiu P, Hanabuchi S, Lu Y, Wang Z, Liu Z, Li H, He J, Lin P, Weber D, Davis RE, Kwak L, Cai Z, Yi Q (2013) PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma. Leukemia 27(3):702–710. doi: 10.1038/leu.2012.272 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Franqui-Machin R, Wendlandt EB, Janz S, Zhan F, Tricot G (2015) Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? Oncotarget 6(38):40496–40506. doi: 10.18632/oncotarget.5800 PubMedGoogle Scholar
  64. 64.
    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30(7):1073–1081. doi: 10.1093/carcin/bgp127 PubMedCrossRefGoogle Scholar
  65. 65.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. doi: 10.1016/j.cell.2010.01.025 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Chow MT, Moller A, Smyth MJ (2012) Inflammation and immune surveillance in cancer. Semin Cancer Biol 22(1):23–32. doi: 10.1016/j.semcancer.2011.12.004 PubMedCrossRefGoogle Scholar
  67. 67.
    Ridnour LA, Cheng RY, Switzer CH, Heinecke JL, Ambs S, Glynn S, Young HA, Trinchieri G, Wink DA (2013) Molecular pathways: toll-like receptors in the tumor microenvironment—poor prognosis or new therapeutic opportunity. Clin Cancer Res 19(6):1340–1346. doi: 10.1158/1078-0432.ccr-12-0408 PubMedCrossRefGoogle Scholar
  68. 68.
    Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12(4):253–268. doi: 10.1038/nri3175 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Talmadge JE, Gabrilovich DI (2013) History of myeloid-derived suppressor cells. Nat Rev Cancer 13(10):739–752. doi: 10.1038/nrc3581 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Condamine T, Gabrilovich DI (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 32(1):19–25. doi: 10.1016/ PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225. doi: 10.1038/nature10138 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL (2008) Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13(1):23–35. doi: 10.1016/j.ccr.2007.12.004 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol 181(7):4666–4675PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Watson GA, Fu YX, Lopez DM (1991) Splenic macrophages from tumor-bearing mice co-expressing MAC-1 and MAC-2 antigens exert immunoregulatory functions via two distinct mechanisms. J Leukoc Biol 49(2):126–138PubMedGoogle Scholar
  75. 75.
    Kusmartsev SA, Li Y, Chen SH (2000) Gr-1 + myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol 165(2):779–785PubMedCrossRefGoogle Scholar
  76. 76.
    Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, Antonia S, Ochoa JB, Ochoa AC (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849. doi: 10.1158/0008-5472.can-04-0465 PubMedCrossRefGoogle Scholar
  77. 77.
    Serafini P, Mgebroff S, Noonan K, Borrello I (2008) Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. Cancer Res 68(13):5439–5449. doi: 10.1158/0008-5472.can-07-6621 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70(1):99–108. doi: 10.1158/0008-5472.can-09-1882 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, Divino CM, Chen SH (2006) Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 66(2):1123–1131. doi: 10.1158/0008-5472.can-05-1299 PubMedCrossRefGoogle Scholar
  80. 80.
    Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, Matrisian LM, Carbone DP, Lin PC (2004) Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421. doi: 10.1016/j.ccr.2004.08.031 PubMedCrossRefGoogle Scholar
  81. 81.
    Ramachandran IR, Martner A, Pisklakova A, Condamine T, Chase T, Vogl T, Roth J, Gabrilovich D, Nefedova Y (2013) Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol 190(7):3815–3823. doi: 10.4049/jimmunol.1203373 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Van Valckenborgh E, Schouppe E, Movahedi K, De Bruyne E, Menu E, De Baetselier P, Vanderkerken K, Van Ginderachter JA (2012) Multiple myeloma induces the immunosuppressive capacity of distinct myeloid-derived suppressor cell subpopulations in the bone marrow. Leukemia 26(11):2424–2428. doi: 10.1038/leu.2012.113 PubMedCrossRefGoogle Scholar
  83. 83.
    De Veirman K, Van Valckenborgh E, Lahmar Q, Geeraerts X, De Bruyne E, Menu E, Van Riet I, Vanderkerken K, Van Ginderachter JA (2014) Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front Oncol 4:349. doi: 10.3389/fonc.2014.00349 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Brimnes MK, Vangsted AJ, Knudsen LM, Gimsing P, Gang AO, Johnsen HE, Svane IM (2010) Increased level of both CD4+FOXP3+ regulatory T cells and CD14+HLA-DR(-)/low myeloid-derived suppressor cells and decreased level of dendritic cells in patients with multiple myeloma. Scand J Immunol 72(6):540–547. doi: 10.1111/j.1365-3083.2010.02463.x PubMedCrossRefGoogle Scholar
  85. 85.
    Gorgun GT, Whitehill G, Anderson JL, Hideshima T, Maguire C, Laubach J, Raje N, Munshi NC, Richardson PG, Anderson KC (2013) Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121(15):2975–2987. doi: 10.1182/blood-2012-08-448548 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Favaloro J, Liyadipitiya T, Brown R, Yang S, Suen H, Woodland N, Nassif N, Hart D, Fromm P, Weatherburn C, Gibson J, Ho PJ, Joshua D (2014) Myeloid derived suppressor cells are numerically, functionally and phenotypically different in patients with multiple myeloma. Leuk Lymphoma 55(12):2893–2900. doi: 10.3109/10428194.2014.904511 PubMedCrossRefGoogle Scholar
  87. 87.
    De Keersmaecker B, Fostier K, Corthals J, Wilgenhof S, Heirman C, Aerts JL, Thielemans K, Schots R (2014) Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation. Cancer Immunol Immunother: CII 63(10):1023–1036. doi: 10.1007/s00262-014-1571-6 PubMedCrossRefGoogle Scholar
  88. 88.
    Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78. doi: 10.1038/nrc1256 PubMedCrossRefGoogle Scholar
  89. 89.
    Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61. doi: 10.1016/j.immuni.2014.06.010 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Komohara Y, Jinushi M, Takeya M (2014) Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci 105(1):1–8. doi: 10.1111/cas.12314 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Suyani E, Sucak GT, Akyurek N, Sahin S, Baysal NA, Yagci M, Haznedar R (2013) Tumor-associated macrophages as a prognostic parameter in multiple myeloma. Ann Hematol 92(5):669–677. doi: 10.1007/s00277-012-1652-6 PubMedCrossRefGoogle Scholar
  92. 92.
    Van Overmeire E, Laoui D, Keirsse J, Van Ginderachter JA, Sarukhan A (2014) Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues. Front Immunol 5:127. doi: 10.3389/fimmu.2014.00127 PubMedPubMedCentralGoogle Scholar
  93. 93.
    Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, Mack M, Pipeleers D, In’t Veld P, De Baetselier P, Van Ginderachter JA (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70(14):5728–5739. doi: 10.1158/0008-5472.can-09-4672 PubMedCrossRefGoogle Scholar
  94. 94.
    Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO (2014) The cellular and molecular origin of tumor-associated macrophages. Science (New York, NY) 344(6186):921–925. doi: 10.1126/science.1252510 CrossRefGoogle Scholar
  95. 95.
    Hume DA, MacDonald KP (2012) Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood 119(8):1810–1820. doi: 10.1182/blood-2011-09-379214 PubMedCrossRefGoogle Scholar
  96. 96.
    Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, Karroum O, Jordan B, Carmeliet P, Gysemans C, De Baetselier P, Mazzone M, Van Ginderachter JA (2014) Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74(1):24–30. doi: 10.1158/0008-5472.can-13-1196 PubMedCrossRefGoogle Scholar
  97. 97.
    Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E, Quiceno DG, Padhya T, McCaffrey TV, McCaffrey JC, Gabrilovich DI (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207(11):2439–2453. doi: 10.1084/jem.20100587 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Scavelli C, Nico B, Cirulli T, Ria R, Di Pietro G, Mangieri D, Bacigalupo A, Mangialardi G, Coluccia AM, Caravita T, Molica S, Ribatti D, Dammacco F, Vacca A (2008) Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma. Oncogene 27(5):663–674. doi: 10.1038/sj.onc.1210691 PubMedCrossRefGoogle Scholar
  99. 99.
    Costes V, Portier M, Lu Z-Y, Rossi J-F, Bataille R, Klein B (1998) Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production. Br J Haematol 103(4):1152–1160. doi: 10.1046/j.1365-2141.1998.01101.x PubMedCrossRefGoogle Scholar
  100. 100.
    Hope C, Ollar SJ, Heninger E, Hebron E, Jensen JL, Kim J, Maroulakou I, Miyamoto S, Leith C, Yang DT, Callander N, Hematti P, Chesi M, Bergsagel PL, Asimakopoulos F (2014) TPL2 kinase regulates the inflammatory milieu of the myeloma niche. Blood 123(21):3305–3315. doi: 10.1182/blood-2014-02-554071 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Otsuki T, Yata K, Sakaguchi H, Uno M, Fujii T, Wada H, Sugihara T, Ueki A (2002) IL-10 in myeloma cells. Leuk Lymphoma 43(5):969–974PubMedCrossRefGoogle Scholar
  102. 102.
    Ribatti D, Nico B, Vacca A (2006) Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 25(31):4257–4266. doi: 10.1038/sj.onc.1209456 PubMedCrossRefGoogle Scholar
  103. 103.
    Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22(11):633–640PubMedCrossRefGoogle Scholar
  104. 104.
    Garcia-Sanz R, Gonzalez M, Orfao A, Moro MJ, Hernandez JM, Borrego D, Carnero M, Casanova F, Barez A, Jimenez R, Portero JA, San Miguel JF (1996) Analysis of natural killer-associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications. Br J Haematol 93(1):81–88PubMedCrossRefGoogle Scholar
  105. 105.
    Guillerey C, Ferrari de Andrade L, Vuckovic S, Miles K, Ngiow SF, Yong MC, Teng MW, Colonna M, Ritchie DS, Chesi M, Bergsagel PL, Hill GR, Smyth MJ, Martinet L (2015) Immunosurveillance and therapy of multiple myeloma are CD226 dependent. J Clin Investig 125(5):2077–2089. doi: 10.1172/JCI77181 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Ponzetta A, Benigni G, Antonangeli F, Sciume G, Sanseviero E, Zingoni A, Ricciardi MR, Petrucci MT, Santoni A, Bernardini G (2015) Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment. Cancer Res. doi: 10.1158/0008-5472.CAN-15-1320 PubMedGoogle Scholar
  107. 107.
    El-Sherbiny YM, Meade JL, Holmes TD, McGonagle D, Mackie SL, Morgan AW, Cook G, Feyler S, Richards SJ, Davies FE, Morgan GJ, Cook GP (2007) The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer Res 67(18):8444–8449. doi: 10.1158/0008-5472.CAN-06-4230 PubMedCrossRefGoogle Scholar
  108. 108.
    Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, Groh V, Spies T, Pollio G, Cosman D, Catalano L, Tassone P, Rotoli B, Venuta S (2005) HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood 105(1):251–258. doi: 10.1182/blood-2004-04-1422 PubMedCrossRefGoogle Scholar
  109. 109.
    Frohn C, Hoppner M, Schlenke P, Kirchner H, Koritke P, Luhm J (2002) Anti-myeloma activity of natural killer lymphocytes. Br J Haematol 119(3):660–664PubMedCrossRefGoogle Scholar
  110. 110.
    Soriani A, Zingoni A, Cerboni C, Iannitto ML, Ricciardi MR, Di Gialleonardo V, Cippitelli M, Fionda C, Petrucci MT, Guarini A, Foa R, Santoni A (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113(15):3503–3511. doi: 10.1182/blood-2008-08-173914 PubMedCrossRefGoogle Scholar
  111. 111.
    Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5(3):201–214. doi: 10.1038/nri1570 PubMedCrossRefGoogle Scholar
  112. 112.
    Ikeda H, Old LJ, Schreiber RD (2002) The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 13(2):95–109PubMedCrossRefGoogle Scholar
  113. 113.
    Portier M, Zhang XG, Caron E, Lu ZY, Bataille R, Klein B (1993) gamma-Interferon in multiple myeloma: inhibition of interleukin-6 (IL-6)-dependent myeloma cell growth and downregulation of IL-6-receptor expression in vitro. Blood 81(11):3076–3082PubMedGoogle Scholar
  114. 114.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 408(6812):600–605. doi: 10.1038/35046102 PubMedCrossRefGoogle Scholar
  115. 115.
    Viel S, Charrier E, Marcais A, Rouzaire P, Bienvenu J, Karlin L, Salles G, Walzer T (2013) Monitoring NK cell activity in patients with hematological malignancies. Oncoimmunology 2(9):e26011. doi: 10.4161/onci.26011 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ (2011) Natural innate and adaptive immunity to cancer. Annu Rev Immunol 29:235–271. doi: 10.1146/annurev-immunol-031210-101324 PubMedCrossRefGoogle Scholar
  117. 117.
    Bernal M, Garrido P, Jimenez P, Carretero R, Almagro M, Lopez P, Navarro P, Garrido F, Ruiz-Cabello F (2009) Changes in activatory and inhibitory natural killer (NK) receptors may induce progression to multiple myeloma: implications for tumor evasion of T and NK cells. Hum Immunol 70(10):854–857. doi: 10.1016/j.humimm.2009.07.004 PubMedCrossRefGoogle Scholar
  118. 118.
    Jinushi M, Vanneman M, Munshi NC, Tai YT, Prabhala RH, Ritz J, Neuberg D, Anderson KC, Carrasco DR, Dranoff G (2008) MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proc Natl Acad Sci USA 105(4):1285–1290. doi: 10.1073/pnas.0711293105 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Perez-Andres M, Almeida J, Martin-Ayuso M, Moro MJ, Martin-Nunez G, Galende J, Borrego D, Rodriguez MJ, Ortega F, Hernandez J, Moreno I, Dominguez M, Mateo G, San Miguel JF, Orfao A, Spanish Network on multiple m, Spanish Network of Cancer Research C (2005) Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment. Leukemia 19(3):449–455. doi: 10.1038/sj.leu.2403647 PubMedCrossRefGoogle Scholar
  120. 120.
    von Lilienfeld-Toal M, Frank S, Leyendecker C, Feyler S, Jarmin S, Morgan R, Glasmacher A, Marten A, Schmidt-Wolf IG, Brossart P, Cook G (2010) Reduced immune effector cell NKG2D expression and increased levels of soluble NKG2D ligands in multiple myeloma may not be causally linked. Cancer Immunol Immunother: CII 59(6):829–839. doi: 10.1007/s00262-009-0807-3 CrossRefGoogle Scholar
  121. 121.
    Fauriat C, Mallet F, Olive D, Costello RT (2006) Impaired activating receptor expression pattern in natural killer cells from patients with multiple myeloma. Leukemia 20(4):732–733. doi: 10.1038/sj.leu.2404096 PubMedCrossRefGoogle Scholar
  122. 122.
    Mills KH, Cawley JC (1983) Abnormal monoclonal antibody-defined helper/suppressor T-cell subpopulations in multiple myeloma: relationship to treatment and clinical stage. Br J Haematol 53(2):271–275PubMedCrossRefGoogle Scholar
  123. 123.
    Cook G, Campbell JD (1999) Immune regulation in multiple myeloma: the host-tumour conflict. Blood Rev 13(3):151–162. doi: 10.1054/blre.1999.0111 PubMedCrossRefGoogle Scholar
  124. 124.
    Pinzon-Charry A, Maxwell T, Lopez JA (2005) Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 83(5):451–461. doi: 10.1111/j.1440-1711.2005.01371.x PubMedCrossRefGoogle Scholar
  125. 125.
    Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hammerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V (2003) Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med 9(9):1151–1157. doi: 10.1038/nm914 PubMedCrossRefGoogle Scholar
  126. 126.
    Raje N, Gong J, Chauhan D, Teoh G, Avigan D, Wu Z, Chen D, Treon SP, Webb IJ, Kufe DW, Anderson KC (1999) Bone marrow and peripheral blood dendritic cells from patients with multiple myeloma are phenotypically and functionally normal despite the detection of Kaposi’s sarcoma herpesvirus gene sequences. Blood 93(5):1487–1495PubMedGoogle Scholar
  127. 127.
    Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J, Ho PJ, Hart D, Joshua D (2001) Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 98(10):2992–2998PubMedCrossRefGoogle Scholar
  128. 128.
    Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B, Fogli M, Ferri E, Della Cuna GR, Tura S, Baccarani M, Lemoli RM (2002) Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 100(1):230–237PubMedCrossRefGoogle Scholar
  129. 129.
    Brimnes MK, Svane IM, Johnsen HE (2006) Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clin Exp Immunol 144(1):76–84. doi: 10.1111/j.1365-2249.2006.03037.x PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Leone P, Berardi S, Frassanito MA, Ria R, De Re V, Cicco S, Battaglia S, Ditonno P, Dammacco F, Vacca A, Racanelli V (2015) Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing. Blood 126(12):1443–1451. doi: 10.1182/blood-2015-01-623975 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J (2003) Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19(2):225–234PubMedCrossRefGoogle Scholar
  132. 132.
    Chauhan D, Singh AV, Brahmandam M, Carrasco R, Bandi M, Hideshima T, Bianchi G, Podar K, Tai YT, Mitsiades C, Raje N, Jaye DL, Kumar SK, Richardson P, Munshi N, Anderson KC (2009) Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 16(4):309–323. doi: 10.1016/j.ccr.2009.08.019 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Halapi E, Werner A, Wahlstrom J, Osterborg A, Jeddi-Tehrani M, Yi Q, Janson CH, Wigzell H, Grunewald J, Mellstedt H (1997) T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden. Eur J Immunol 27(9):2245–2252. doi: 10.1002/eji.1830270919 PubMedCrossRefGoogle Scholar
  134. 134.
    Dhodapkar MV, Krasovsky J, Olson K (2002) T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells. Proc Natl Acad Sci USA 99(20):13009–13013. doi: 10.1073/pnas.202491499 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wen YJ, Min R, Tricot G, Barlogie B, Yi Q (2002) Tumor lysate-specific cytotoxic T lymphocytes in multiple myeloma: promising effector cells for immunotherapy. Blood 99(9):3280–3285PubMedCrossRefGoogle Scholar
  136. 136.
    Dhodapkar MV, Krasovsky J, Osman K, Geller MD (2003) Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J Exp Med 198(11):1753–1757. doi: 10.1084/jem.20031030 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Spisek R, Kukreja A, Chen LC, Matthews P, Mazumder A, Vesole D, Jagannath S, Zebroski HA, Simpson AJ, Ritter G, Durie B, Crowley J, Shaughnessy JD Jr, Scanlan MJ, Gure AO, Barlogie B, Dhodapkar MV (2007) Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med 204(4):831–840. doi: 10.1084/jem.20062387 PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Bryant C, Suen H, Brown R, Yang S, Favaloro J, Aklilu E, Gibson J, Ho PJ, Iland H, Fromm P, Woodland N, Nassif N, Hart D, Joshua DE (2013) Long-term survival in multiple myeloma is associated with a distinct immunological profile, which includes proliferative cytotoxic T-cell clones and a favourable Treg/Th17 balance. Blood Cancer J 3:e148. doi: 10.1038/bcj.2013.34 PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Bogen B, Ruffini PA, Corthay A, Fredriksen AB, Froyland M, Lundin K, Rosjo E, Thompson K, Massaia M (2006) Idiotype-specific immunotherapy in multiple myeloma: suggestions for future directions of research. Haematologica 91(7):941–948PubMedGoogle Scholar
  140. 140.
    Bogen B, Schenck K, Munthe LA, Dembic Z (2000) Deletion of idiotype (Id)-specific T cells in multiple myeloma. Acta Oncol 39(7):783–788PubMedCrossRefGoogle Scholar
  141. 141.
    Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, June CH (2015) NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21(8):914–921. doi: 10.1038/nm.3910 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Yi Q, Osterborg A, Bergenbrant S, Mellstedt H, Holm G, Lefvert AK (1995) Idiotype-reactive T-cell subsets and tumor load in monoclonal gammopathies. Blood 86(8):3043–3049PubMedGoogle Scholar
  143. 143.
    Sharma A, Khan R, Joshi S, Kumar L, Sharma M (2010) Dysregulation in T helper 1/T helper 2 cytokine ratios in patients with multiple myeloma. Leuk Lymphoma 51(5):920–927. doi: 10.3109/10428191003699563 PubMedCrossRefGoogle Scholar
  144. 144.
    Frassanito MA, Cusmai A, Dammacco F (2001) Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Exp Immunol 125(2):190–197PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Ogawara H, Handa H, Yamazaki T, Toda T, Yoshida K, Nishimoto N, Al-ma’Quol WH, Kaneko Y, Matsushima T, Tsukamoto N, Nojima Y, Matsumoto M, Sawamura M, Murakami H (2005) High Th1/Th2 ratio in patients with multiple myeloma. Leuk Res 29(2):135–140. doi: 10.1016/j.leukres.2004.06.003 PubMedCrossRefGoogle Scholar
  146. 146.
    Murakami H, Ogawara H, Hiroshi H (2004) Th1/Th2 cells in patients with multiple myeloma. Hematology 9(1):41–45. doi: 10.1080/10245330310001652437 PubMedCrossRefGoogle Scholar
  147. 147.
    Feng P, Yan R, Dai X, Xie X, Wen H, Yang S (2015) The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma. Inflammation 38(2):705–709. doi: 10.1007/s10753-014-9980-4 PubMedCrossRefGoogle Scholar
  148. 148.
    Prabhala RH, Neri P, Bae JE, Tassone P, Shammas MA, Allam CK, Daley JF, Chauhan D, Blanchard E, Thatte HS, Anderson KC, Munshi NC (2006) Dysfunctional T regulatory cells in multiple myeloma. Blood 107(1):301–304. doi: 10.1182/blood-2005-08-3101 PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA, Classen S, Schultze JL (2006) In vivo peripheral expansion of naive CD4+CD25 high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 107(10):3940–3949. doi: 10.1182/blood-2005-09-3671 PubMedCrossRefGoogle Scholar
  150. 150.
    Giannopoulos K, Kaminska W, Hus I, Dmoszynska A (2012) The frequency of T regulatory cells modulates the survival of multiple myeloma patients: detailed characterisation of immune status in multiple myeloma. Br J Cancer 106(3):546–552. doi: 10.1038/bjc.2011.575 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Braga WM, Atanackovic D, Colleoni GW (2012) The role of regulatory T cells and TH17 cells in multiple myeloma. Clin Dev Immunol 2012:293479. doi: 10.1155/2012/293479 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Shen CJ, Yuan ZH, Liu YX, Hu GY (2012) Increased numbers of T helper 17 cells and the correlation with clinicopathological characteristics in multiple myeloma. J Int Med Res 40(2):556–564PubMedCrossRefGoogle Scholar
  153. 153.
    Di Lullo G, Marcatti M, Heltai S, Brunetto E, Tresoldi C, Bondanza A, Bonini C, Ponzoni M, Tonon G, Ciceri F, Bordignon C, Protti MP (2015) Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival. Oncoimmunology 4(5):e1005460. doi: 10.1080/2162402X.2015.1005460 PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    McEwen-Smith RM, Salio M, Cerundolo V (2015) The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol Res 3(5):425–435. doi: 10.1158/2326-6066.CIR-15-0062 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Song W, van der Vliet HJ, Tai YT, Prabhala R, Wang R, Podar K, Catley L, Shammas MA, Anderson KC, Balk SP, Exley MA, Munshi NC (2008) Generation of antitumor invariant natural killer T cell lines in multiple myeloma and promotion of their functions via lenalidomide: a strategy for immunotherapy. Clin Cancer Res 14(21):6955–6962. doi: 10.1158/1078-0432.CCR-07-5290 PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Chang DH, Deng H, Matthews P, Krasovsky J, Ragupathi G, Spisek R, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV (2008) Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer. Blood 112(4):1308–1316. doi: 10.1182/blood-2008-04-149831 PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Dhodapkar MV, Geller MD, Chang DH, Shimizu K, Fujii S, Dhodapkar KM, Krasovsky J (2003) A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 197(12):1667–1676. doi: 10.1084/jem.20021650 PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Godfrey DI, Uldrich AP, McCluskey J, Rossjohn J, Moody DB (2015) The burgeoning family of unconventional T cells. Nat Immunol 16(11):1114–1123. doi: 10.1038/ni.3298 PubMedCrossRefGoogle Scholar
  159. 159.
    Pratt G, Goodyear O, Moss P (2007) Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol 138(5):563–579. doi: 10.1111/j.1365-2141.2007.06705.x PubMedCrossRefGoogle Scholar
  160. 160.
    Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111(5):2516–2520. doi: 10.1182/blood-2007-10-116129 PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Jimenez-Zepeda VH, Reece DE, Trudel S, Chen C, Franke N, Winter A, Tiedemann R, Kukreti V (2015) Absolute lymphocyte count as predictor of overall survival for patients with multiple myeloma treated with single autologous stem cell transplant. Leuk Lymphoma. doi: 10.3109/10428194.2014.1003057 Google Scholar
  162. 162.
    Wolniak KL, Goolsby CL, Chen YH, Chenn A, Singhal S, LA JayeshMehta Peterson (2013) Expansion of a clonal CD8+CD57+ large granular lymphocyte population after autologous stem cell transplant in multiple myeloma. Am J Clin Pathol 139(2):231–241. doi: 10.1309/AJCP1T0JPBLSLAQF PubMedCrossRefGoogle Scholar
  163. 163.
    Noonan KA, Huff CA, Davis J, Lemas MV, Fiorino S, Bitzan J, Ferguson A, Emerling A, Luznik L, Matsui W, Powell J, Fuchs E, Rosner GL, Epstein C, Rudraraju L, Ambinder RF, Jones RJ, Pardoll D, Borrello I (2015) Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med 7(288):288ra278. doi: 10.1126/scitranslmed.aaa7014 CrossRefGoogle Scholar
  164. 164.
    Karp Leaf R, Cho HJ, Avigan D (2015) Immunotherapy for multiple myeloma, past, present, and future: monoclonal antibodies, vaccines, and cellular therapies. Curr Hematol Malig Rep. doi: 10.1007/s11899-015-0283-0 PubMedGoogle Scholar
  165. 165.
    Wang L, Jin N, Schmitt A, Greiner J, Malcherek G, Hundemer M, Mani J, Hose D, Raab MS, Ho AD, Chen BA, Goldschmidt H, Schmitt M (2015) T cell-based targeted immunotherapies for patients with multiple myeloma. Int J Cancer J Int Cancer 136(8):1751–1768. doi: 10.1002/ijc.29190 CrossRefGoogle Scholar
  166. 166.
    Freeman LM, Lam A, Petcu E, Smith R, Salajegheh A, Diamond P, Zannettino A, Evdokiou A, Luff J, Wong PF, Khalil D, Waterhouse N, Vari F, Rice AM, Catley L, Hart DN, Vuckovic S (2011) Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8+CD4+ T cells: evidence from myeloma-bearing mouse model. J Immunol 187(8):3987–3996. doi: 10.4049/jimmunol.1101202 PubMedCrossRefGoogle Scholar
  167. 167.
    Bensinger W (2014) Allogeneic stem cell transplantation for multiple myeloma. Hematol Oncol Clin N Am 28(5):891–902. doi: 10.1016/j.hoc.2014.06.001 CrossRefGoogle Scholar
  168. 168.
    Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL, Fonseca R, Hayman SR, Lust JA, Kyle RA, Greipp PR, Witzig TE, Rajkumar SV (2003) Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 78(1):34–39. doi: 10.4065/78.1.34 PubMedCrossRefGoogle Scholar
  169. 169.
    Kumar S, Witzig TE, Dispenzieri A, Lacy MQ, Wellik LE, Fonseca R, Lust JA, Gertz MA, Kyle RA, Greipp PR, Rajkumar SV (2004) Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma. Leukemia 18(3):624–627. doi: 10.1038/sj.leu.2403285 PubMedCrossRefGoogle Scholar
  170. 170.
    Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96(9):2943–2950PubMedGoogle Scholar
  171. 171.
    Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163(1):380–386PubMedGoogle Scholar
  172. 172.
    Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ, Prince HM (2010) Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 24(1):22–32. doi: 10.1038/leu.2009.236 PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Gorgun G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, Cirstea D, Santo L, Hu Y, Tai YT, Nahar S, Mimura N, Fabre C, Raje N, Munshi N, Richardson P, Anderson KC (2010) Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 116(17):3227–3237. doi: 10.1182/blood-2010-04-279893 PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T, Vasir B, Arnason J, Tzachanis D, Zwicker JI, Joyce RM, Levine JD, Anderson KC, Kufe D, Avigan D (2013) Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother: CII 62(1):39–49. doi: 10.1007/s00262-012-1308-3 PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98(1):210–216PubMedCrossRefGoogle Scholar
  176. 176.
    Jungkunz-Stier I, Zekl M, Stuhmer T, Einsele H, Seggewiss-Bernhardt R (2014) Modulation of natural killer cell effector functions through lenalidomide/dasatinib and their combined effects against multiple myeloma cells. Leuk Lymphoma 55(1):168–176. doi: 10.3109/10428194.2013.794270 PubMedCrossRefGoogle Scholar
  177. 177.
    Zhu D, Corral LG, Fleming YW, Stein B (2008) Immunomodulatory drugs revlimid (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother: CII 57(12):1849–1859. doi: 10.1007/s00262-008-0512-7 PubMedCrossRefGoogle Scholar
  178. 178.
    Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N, Kumar S, Chauhan D, Treon SP, Richardson P, Anderson KC (2005) Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 128(2):192–203. doi: 10.1111/j.1365-2141.2004.05286.x PubMedCrossRefGoogle Scholar
  179. 179.
    Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, Jagannath S, Dhodapkar MV (2006) Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 108(2):618–621. doi: 10.1182/blood-2005-10-4184 PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Minnema MC, van der Veer MS, Aarts T, Emmelot M, Mutis T, Lokhorst HM (2009) Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4+Foxp3+ T cells. Leukemia 23(3):605–607. doi: 10.1038/leu.2008.247 PubMedCrossRefGoogle Scholar
  181. 181.
    Spina F, Montefusco V, Crippa C, Citro A, Sammassimo S, Olivero B, Gentili S, Galli M, Guglielmelli T, Rossi D, Falcone AP, Grasso M, Patriarca F, De Muro M, Corradini P (2011) Lenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple chemotherapy lines, in particular after allogeneic transplant. Leuk Lymphoma 52(7):1262–1270. doi: 10.3109/10428194.2011.564695 PubMedCrossRefGoogle Scholar
  182. 182.
    Lioznov M, El-Cheikh J Jr, Hoffmann F, Hildebrandt Y, Ayuk F, Wolschke C, Atanackovic D, Schilling G, Badbaran A, Bacher U, Fehse B, Zander AR, Blaise D, Mohty M, Kroger N (2010) Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transpl 45(2):349–353. doi: 10.1038/bmt.2009.155 CrossRefGoogle Scholar
  183. 183.
    Nencioni A, Grunebach F, Patrone F, Ballestrero A, Brossart P (2007) Proteasome inhibitors: antitumor effects and beyond. Leukemia 21(1):30–36. doi: 10.1038/sj.leu.2404444 PubMedCrossRefGoogle Scholar
  184. 184.
    Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127(2):165–172. doi: 10.1111/j.1365-2141.2004.05188.x PubMedCrossRefGoogle Scholar
  185. 185.
    Pellom ST Jr, Dudimah DF, Thounaojam MC, Sayers TJ, Shanker A (2015) Modulatory effects of bortezomib on host immune cell functions. Immunotherapy. doi: 10.2217/imt.15.66 PubMedGoogle Scholar
  186. 186.
    Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE, Storrie B, Mulder A, Shaughnessy JD Jr, Barlogie B, van Rhee F (2008) Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood 111(3):1309–1317. doi: 10.1182/blood-2007-03-078535 PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV (2007) Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood 109(11):4839–4845. doi: 10.1182/blood-2006-10-054221 PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, Mitsiades C, Mitsiades N, Yasui H, Letai A, Ovaa H, Berkers C, Nicholson B, Chao TH, Neuteboom ST, Richardson P, Palladino MA, Anderson KC (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8(5):407–419. doi: 10.1016/j.ccr.2005.10.013 PubMedCrossRefGoogle Scholar
  189. 189.
    Nencioni A, Schwarzenberg K, Brauer KM, Schmidt SM, Ballestrero A, Grunebach F, Brossart P (2006) Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood 108(2):551–558. doi: 10.1182/blood-2005-08-3494 PubMedCrossRefGoogle Scholar
  190. 190.
    Feng X, Yan J, Wang Y, Zierath JR, Nordenskjold M, Henter JI, Fadeel B, Zheng C (2010) The proteasome inhibitor bortezomib disrupts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and natural killer (NK) cell killing of TRAIL receptor-positive multiple myeloma cells. Mol Immunol 47(14):2388–2396. doi: 10.1016/j.molimm.2010.05.003 PubMedCrossRefGoogle Scholar
  191. 191.
    Lundqvist A, Yokoyama H, Smith A, Berg M, Childs R (2009) Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells. Blood 113(24):6120–6127. doi: 10.1182/blood-2008-11-190421 PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Sun K, Welniak LA, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Liu H, Barao I, Riordan W, Sitcheran R, Wysocki C, Serody JS, Blazar BR, Sayers TJ, Murphy WJ (2004) Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA 101(21):8120–8125. doi: 10.1073/pnas.0401563101 PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Sun K, Wilkins DE, Anver MR, Sayers TJ, Panoskaltsis-Mortari A, Blazar BR, Welniak LA, Murphy WJ (2005) Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood 106(9):3293–3299. doi: 10.1182/blood-2004-11-4526 PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR (2006) NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood 107(2):827–834. doi: 10.1182/blood-2005-05-1820 PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    McBride A, Klaus JO, Stockerl-Goldstein K (2015) Carfilzomib: a second-generation proteasome inhibitor for the treatment of multiple myeloma. Am J Health-Syst Pharm: AJHP 72(5):353–360. doi: 10.2146/ajhp130281 PubMedCrossRefGoogle Scholar
  196. 196.
    Porrata LF, Litzow MR, Markovic SN (2001) Immune reconstitution after autologous hematopoietic stem cell transplantation. Mayo Clin Proc 76(4):407–412. doi: 10.4065/76.4.407 PubMedCrossRefGoogle Scholar
  197. 197.
    Kroger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, Shimoni A, Nagler A, Binder T, Eiermann T, Madrigal A, Schwerdtfeger R, Kiehl M, Sayer HG, Beyer J, Bornhauser M, Ayuk F, Zander AR, Marks DI, Clinical Trial Committee of the British Society of B, Marrow T, the German Cooperative Transplant G (2005) Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol 129(5):631–643. doi: 10.1111/j.1365-2141.2005.05513.x PubMedCrossRefGoogle Scholar
  198. 198.
    Shi J, Tricot G, Szmania S, Rosen N, Garg TK, Malaviarachchi PA, Moreno A, Dupont B, Hsu KC, Baxter-Lowe LA, Cottler-Fox M, Shaughnessy JD Jr, Barlogie B, van Rhee F (2008) Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol 143(5):641–653. doi: 10.1111/j.1365-2141.2008.07340.x PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, Farag SS (2012) A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 120(22):4324–4333. doi: 10.1182/blood-2012-06-438028 PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Benson DM Jr, Cohen AD, Jagannath S, Munshi NC, Spitzer G, Hofmeister CC, Efebera YA, Andre P, Zerbib R, Caligiuri MA (2015) A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin Cancer Res 21(18):4055–4061. doi: 10.1158/1078-0432.CCR-15-0304 PubMedCrossRefGoogle Scholar
  201. 201.
    Jiang H, Zhang W, Shang P, Zhang H, Fu W, Ye F, Zeng T, Huang H, Zhang X, Sun W, Man-Yuen Sze D, Yi Q, Hou J (2014) Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol 8(2):297–310. doi: 10.1016/j.molonc.2013.12.001 PubMedCrossRefGoogle Scholar
  202. 202.
    Richardson PG, Lonial S, Jakubowiak AJ, Harousseau JL, Anderson KC (2011) Monoclonal antibodies in the treatment of multiple myeloma. Br J Haematol 154(6):745–754. doi: 10.1111/j.1365-2141.2011.08790.x PubMedCrossRefGoogle Scholar
  203. 203.
    Laubach JP, Tai YT, Richardson PG, Anderson KC (2014) Daratumumab granted breakthrough drug status. Expert Opin Investig Drugs 23(4):445–452. doi: 10.1517/13543784.2014.889681 PubMedCrossRefGoogle Scholar
  204. 204.
    Starr P (2015) Elotuzumab, first-in-class monoclonal antibody immunotherapy, improves outcomes in patients with multiple myeloma. Am Health Drug Benefits 8(Spec Issue):17PubMedPubMedCentralGoogle Scholar
  205. 205.
    Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB (2008) CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 14(9):2775–2784. doi: 10.1158/1078-0432.CCR-07-4246 PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Collins SM, Bakan CE, Swartzel GD, Hofmeister CC, Efebera YA, Kwon H, Starling GC, Ciarlariello D, Bhaskar S, Briercheck EL, Hughes T, Yu J, Rice A, Benson DM Jr (2013) Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother: CII 62(12):1841–1849. doi: 10.1007/s00262-013-1493-8 PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133. doi: 10.1056/NEJMoa1302369 PubMedCrossRefGoogle Scholar
  208. 208.
    Armand P (2015) Immune checkpoint blockade in hematologic malignancies. Blood 125(22):3393–3400. doi: 10.1182/blood-2015-02-567453 PubMedCrossRefGoogle Scholar
  209. 209.
    Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, Joyce RM, Wellenstein K, Keefe W, Schickler M, Rotem-Yehudar R, Kufe D, Avigan D (2011) PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 34(5):409–418. doi: 10.1097/CJI.0b013e31821ca6ce PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13):2286–2294. doi: 10.1182/blood-2010-02-271874 PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Jing W, Gershan JA, Weber J, Tlomak D, McOlash L, Sabatos-Peyton C, Johnson BD (2015) Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma. J Immunother Cancer 3(1):2. doi: 10.1186/s40425-014-0043-z PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazon A, Azpilikueta A, Ochoa MC, Alfaro C, Solano S, Perez-Gracia JL, Oyajobi BO, Melero I (2008) Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 14(21):6895–6906. doi: 10.1158/1078-0432.CCR-08-0285 PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Lesokhin AM, Callahan MK, Postow MA, Wolchok JD (2015) On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med 7(280):280sr281. doi: 10.1126/scitranslmed.3010274 CrossRefGoogle Scholar
  214. 214.
    Hoang MD, Jung SH, Lee HJ, Lee YK, Nguyen-Pham TN, Choi NR, Vo MC, Lee SS, Ahn JS, Yang DH, Kim YK, Kim HJ, Lee JJ (2015) Dendritic cell-based cancer immunotherapy against multiple myeloma: from bench to clinic. Chonnam Med J 51(1):1–7. doi: 10.4068/cmj.2015.51.1.1 PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Maus MV, June CH (2014) CARTs on the road for myeloma. Clin Cancer Res 20(15):3899–3901. doi: 10.1158/1078-0432.CCR-14-0721 PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360. doi: 10.1146/annurev.immunol.22.012703.104803 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Camille Guillerey
    • 1
    • 2
  • Kyohei Nakamura
    • 1
  • Slavica Vuckovic
    • 2
    • 3
  • Geoffrey R. Hill
    • 3
  • Mark J. Smyth
    • 1
    • 2
    Email author
  1. 1.Immunology of Cancer and Infection LaboratoryQIMR Berghofer Medical Research InstituteHerstonAustralia
  2. 2.School of MedicineThe University of QueenslandHerstonAustralia
  3. 3.Bone Marrow Transplantation LaboratoryQIMR Berghofer Medical Research InstituteHerstonAustralia

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