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Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma

Leukemia volume 28, pages 993–1000 (2014)Cite this article

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Abstract

The adaptive immune system is clearly capable of recognizing and attacking malignant plasma cells in patients with multiple myeloma (MM). However, MM patients evidence severe defects of humoral and cellular immunity, and it is likely that the profound immune dysregulation typical for this malignancy contributes to its eventual escape from natural immune control. One of the factors responsible for the immune dysfunction in MM might be the programmed death 1 (PD-1) protein. The physiological role of PD-1 is to guarantee T-cell homeostasis by limiting T-cell activation and proliferation. Accordingly, binding of the ligand PD-L1 to PD-1 expressed on the surface of activated T cells delivers an inhibitory signal, reducing cytokine production and proliferation. Using the same mechanism, PD-L1/PD-1 interactions have been shown in a number of animal models to confer tumor escape from immune control. Recently, clinical trials have suggested a significant therapeutic impact of PD-1/PD-L inhibition on a variety of solid tumors—for example, by the application of monoclonal antibodies. We show here that based on (1) the broad expression of PD-1 and its ligands in the microenvironment of myeloma, (2) data indicating an important role of the PD-1 pathway in the immune evasion by MM cells and (3) preclinical results providing a strong rationale for therapeutic PD-1/PD-L inhibition in this malignancy, MM may be very well suited for immunotherapy, for example, a monoclonal antibody, targeting PD-1 and/or its ligands.

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References

  1. Blade J, Cibeira MT, Fernandez de Larrea C, Rosinol L . Multiple myeloma. Ann Oncol 2010; 21: vii313–vii319.

    Article  PubMed  Google Scholar 

  2. Korde N, Kristinsson SY, Landgren O . Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood 2011; 117: 5573–5581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012; 120: 947–959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Quach H, Kalff A, Spencer A . Lenalidomide in multiple myeloma: current status and future potential. Am J Hematol 2012; 87: 1089–1095.

    Article  CAS  PubMed  Google Scholar 

  5. Trono D, Kapanci Y . [Causes of death in cases of lymphoma, myeloma and Hodgkin disease. Study of 218 cases]. Schweiz Med Wochenschr 1983; 113: 701–708.

    CAS  PubMed  Google Scholar 

  6. Kyle RA . Multiple myeloma: review of 869 cases. Mayo Clin Proc 1975; 50: 29–40.

    CAS  PubMed  Google Scholar 

  7. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33.

    Article  PubMed  Google Scholar 

  8. Rutella S, Locatelli F . Targeting multiple-myeloma-induced immune dysfunction to improve immunotherapy outcomes. Clin Dev Immunol 2012; 2012: 196063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Paradisi F, Corti G, Cinelli R . Infections in multiple myeloma. Infect Dis Clin North Am 2001; 15: 373–384,, vii-viii.

    Article  CAS  PubMed  Google Scholar 

  10. Hallek M, Bergsagel PL, Anderson KC . Multiple myeloma: increasing evidence for a multistep transformation process. Blood 1998; 91: 3–21.

    CAS  PubMed  Google Scholar 

  11. Van Riet I . Homing mechanisms of myeloma cells. Pathol Biol (Paris) 1999; 47: 98–108.

    CAS  Google Scholar 

  12. Aggarwal R, Ghobrial IM, Roodman GD . Chemokines in multiple myeloma. Exp Hematol 2006; 34: 1289–1295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cao Y, Luetkens T, Kobold S, Hildebrandt Y, Gordic M, Lajmi N et al. The cytokine/chemokine pattern in the bone marrow environment of multiple myeloma patients. Exp Hematol 2010; 38: 860–867.

    Article  CAS  PubMed  Google Scholar 

  14. Munshi NC . Immunoregulatory mechanisms in multiple myeloma. Hematol Oncol Clin North Am 1997; 11: 51–69.

    Article  CAS  PubMed  Google Scholar 

  15. Broder S, Humphrey R, Durm M, Blackman M, Meade B, Goldman C et al. Impaired synthesis of polyclonal (non-paraprotein) immunoglobulins by circulating lymphocytes from patients with multiple myeloma Role of suppressor cells. N Engl J Med 1975; 293: 887–892.

    Article  CAS  PubMed  Google Scholar 

  16. Nucci M, Anaissie E . Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis 2009; 49: 1211–1225.

    Article  CAS  PubMed  Google Scholar 

  17. Perri RT, Hebbel RP, Oken MM . Influence of treatment and response status on infection risk in multiple myeloma. Am J Med 1981; 71: 935–940.

    Article  CAS  PubMed  Google Scholar 

  18. Schutt P, Brandhorst D, Stellberg W, Poser M, Ebeling P, Muller S et al. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 2006; 47: 1570–1582.

    Article  PubMed  Google Scholar 

  19. Robertson JD, Nagesh K, Jowitt SN, Dougal M, Anderson H, Mutton K et al. Immunogenicity of vaccination against influenza, Streptococcus pneumoniae and Haemophilus influenzae type B in patients with multiple myeloma. Br J Cancer 2000; 82: 1261–1265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kobold S, Luetkens T, Bartels BM, Cao Y, Hildebrandt Y, Sezer O et al. Longitudinal analysis of tetanus- and influenza-specific IgG antibodies in myeloma patients. Clin Dev Immunol 2012; 2012: 134081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chapel HM, Lee M . The use of intravenous immune globulin in multiple myeloma. Clin Exp Immunol 1994; 97: 21–24.

    PubMed  PubMed Central  Google Scholar 

  22. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O . Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2008 (4): CD006501.

  23. Murakami H, Ogawara H, Hiroshi H . Th1/Th2 cells in patients with multiple myeloma. Hematology 2004; 9: 41–45.

    Article  CAS  PubMed  Google Scholar 

  24. Villunger A, Egle A, Marschitz I, Kos M, Bock G, Ludwig H et al. Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance. Blood 1997; 90: 12–20.

    CAS  PubMed  Google Scholar 

  25. Wang S, Yang J, Qian J, Wezeman M, Kwak LW, Yi Q . Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma. Blood 2006; 107: 2432–2439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 2002; 100: 230–237.

    Article  CAS  PubMed  Google Scholar 

  27. Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J et al. 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 2001; 98: 2992–2998.

    Article  CAS  PubMed  Google Scholar 

  28. O'Garra A, Vieira P . Regulatory T cells and mechanisms of immune system control. Nat Med 2004; 10: 801–805.

    Article  CAS  PubMed  Google Scholar 

  29. Zou W . Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006; 6: 295–307.

    Article  CAS  PubMed  Google Scholar 

  30. Prabhala RH, Neri P, Bae JE, Tassone P, Shammas MA, Allam CK et al. Dysfunctional T regulatory cells in multiple myeloma. Blood 2005; 107: 301–304.

    Article  CAS  PubMed  Google Scholar 

  31. Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA et al. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 2006; 107: 3940–3949.

    Article  CAS  PubMed  Google Scholar 

  32. Bonanno G, Mariotti A, Procoli A, Folgiero V, Natale D, De Rosa L et al. Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma. J Transl Med 2012; 10: 247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Amara S, Dezube BJ, Cooley TP, Pantanowitz L, Aboulafia DM . HIV-associated monoclonal gammopathy: a retrospective analysis of 25 patients. Clin Infect Dis 2006; 43: 1198–1205.

    Article  CAS  PubMed  Google Scholar 

  34. Dezube BJ, Aboulafia DM, Pantanowitz L . Plasma cell disorders in HIV-infected patients: from benign gammopathy to multiple myeloma. AIDS Read 2004; 14: 372–374 377–379.

    PubMed  Google Scholar 

  35. Kay NE, Leong TL, Bone N, Vesole DH, Greipp PR, Van Ness B et al. Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients. Blood 2001; 98: 23–28.

    Article  CAS  PubMed  Google Scholar 

  36. Kay NE, Leong T, Bone N, Kyle RA, Greipp PR, Van Ness B et al. T-helper phenotypes in the blood of myeloma patients on ECOG phase III trials E9486/E3A93. Br J Haematol 1998; 100: 459–463.

    Article  CAS  PubMed  Google Scholar 

  37. Corso A, Castelli G, Pagnucco G, Lazzarino M, Bellio L, Klersy C et al. Bone marrow T-cell subsets in patients with monoclonal gammopathies: correlation with clinical stage and disease status. Haematologica 1997; 82: 43–46.

    CAS  PubMed  Google Scholar 

  38. Matta GM, Battaglio S, Dibello C, Napoli P, Baldi C, Ciccone G et al. Polyclonal immunoglobulin E levels are correlated with hemoglobin values and overall survival in patients with multiple myeloma. Clin Cancer Res 2007; 13: 5348–5354.

    Article  CAS  PubMed  Google Scholar 

  39. Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E et al. CD200 is a new prognostic factor in multiple myeloma. Blood 2006; 108: 4194–4197.

    Article  CAS  PubMed  Google Scholar 

  40. Kretz-Rommel A, Qin F, Dakappagari N, Cofiell R, Faas SJ, Bowdish KS . Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy. J Immunol 2008; 180: 699–705.

    Article  CAS  PubMed  Google Scholar 

  41. Muller M, Gounari F, Prifti S, Hacker HJ, Schirrmacher V, Khazaie K . EblacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells. Cancer Res 1998; 58: 5439–5446.

    CAS  PubMed  Google Scholar 

  42. Noonan K, Matsui W, Serafini P, Carbley R, Tan G, Khalili J et al. Activated marrow-infiltrating lymphocytes effectively target plasma cells and their clonogenic precursors. Cancer Res 2005; 65: 2026–2034.

    Article  CAS  PubMed  Google Scholar 

  43. Dhodapkar MV, Krasovsky J, Olson K . 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 2002; 99: 13009–13013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pellat-Deceunynck C, Jego G, Harousseau JL, Vie H, Bataille R . Isolation of human lymphocyte antigens class I-restricted cytotoxic T lymphocytes against autologous myeloma cells. Clin Cancer Res 1999; 5: 705–709.

    CAS  PubMed  Google Scholar 

  45. Hayashi T, Hideshima T, Akiyama M, Raje N, Richardson P, Chauhan D et al. Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes. Blood 2003; 102: 1435–1442.

    Article  CAS  PubMed  Google Scholar 

  46. Lokhorst H, Einsele H, Vesole D, Bruno B, San Miguel J, Perez-Simon JA et al. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol 2010; 28: 4521–4530.

    Article  PubMed  Google Scholar 

  47. Armeson KE, Hill EG, Costa LJ . Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 2012; 48: 562–567.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bjorkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011; 29: 3016–3022.

    Article  PubMed  Google Scholar 

  49. Lokhorst HM, Segeren CM, Verdonck LF, van der Holt B, Raymakers R, van Oers MH et al. Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 2003; 21: 1728–1733.

    Article  PubMed  Google Scholar 

  50. Tricot G, Vesole DH, Jagannath S, Hilton J, Munshi N, Barlogie B . Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–1198.

    CAS  PubMed  Google Scholar 

  51. Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol 2000; 18: 3031–3037.

    Article  CAS  PubMed  Google Scholar 

  52. Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant 2000; 26: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  53. Lokhorst HM, Wu K, Verdonck LF, Laterveer LL, van de Donk NW, van Oers MH et al. The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 2004; 103: 4362–4364.

    Article  CAS  PubMed  Google Scholar 

  54. Biernacki MA, Tai YT, Zhang GL, Alonso A, Zhang W, Prabhala R et al. Novel myeloma-associated antigens revealed in the context of syngeneic hematopoietic stem cell transplantation. Blood 2012; 119: 3142–3150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Broen K, Greupink-Draaisma A, Fredrix H, Schaap N, Dolstra H . Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs. Bone Marrow Transplant 2012; 47: 1229–1234.

    Article  CAS  PubMed  Google Scholar 

  56. Tyler EM, Jungbluth AA, O'Reilly RJ, Koehne G . WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation and donor lymphocyte infusions. Blood 2013; 121: 308–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Orsini E, Bellucci R, Alyea EP, Schlossman R, Canning C, McLaughlin S et al. Expansion of tumor-specific CD8+ T cell clones in patients with relapsed myeloma after donor lymphocyte infusion. Cancer Res 2003; 63: 2561–2568.

    CAS  PubMed  Google Scholar 

  58. Ishida Y, Agata Y, Shibahara K, Honjo T . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11: 3887–3895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996; 8: 765–772.

    Article  CAS  PubMed  Google Scholar 

  60. Keir ME, Freeman GJ, Sharpe AH . PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol 2007; 179: 5064–5070.

    Article  CAS  PubMed  Google Scholar 

  61. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N et al. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 1996; 8: 773–780.

    Article  CAS  PubMed  Google Scholar 

  62. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169: 5538–5545.

    Article  CAS  PubMed  Google Scholar 

  63. Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, Erickson J et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 2002; 9: 133–145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, Weller M et al. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004; 155: 172–182.

    Article  CAS  PubMed  Google Scholar 

  65. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL . PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol 2007; 37: 2405–2410.

    Article  CAS  PubMed  Google Scholar 

  66. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 2002; 32: 634–643.

    Article  CAS  PubMed  Google Scholar 

  67. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Keir ME, Butte MJ, Freeman GJ, Sharpe AH . PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677–704.

    Article  CAS  PubMed  Google Scholar 

  69. Nishimura H, Nose M, Hiai H, Minato N, Honjo T . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11: 141–151.

    Article  CAS  PubMed  Google Scholar 

  70. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001; 291: 319–322.

    Article  CAS  PubMed  Google Scholar 

  71. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793–800.

    Article  CAS  PubMed  Google Scholar 

  72. Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 2006; 8: 190–198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005; 11: 2947–2953.

    Article  CAS  PubMed  Google Scholar 

  74. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N . Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 2006; 108: 19–24.

    Article  PubMed  Google Scholar 

  75. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M . B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004; 10: 5094–5100.

    Article  CAS  PubMed  Google Scholar 

  76. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG . High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 2011; 28: 682–688.

    Article  CAS  PubMed  Google Scholar 

  77. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13: 2151–2157.

    Article  CAS  PubMed  Google Scholar 

  78. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006; 66: 3381–3385.

    Article  CAS  PubMed  Google Scholar 

  79. Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 2013; 49: 2233–2242.

    Article  CAS  PubMed  Google Scholar 

  80. Zhang Y, Huang S, Gong D, Qin Y, Shen Q . Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol 2010; 7: 389–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang SF, Fouquet S, Chapon M, Salmon H, Regnier F, Labroquere K et al. Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors. PLoS One 2011; 6: e17621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chapon M, Randriamampita C, Maubec E, Badoual C, Fouquet S, Wang SF et al. Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol 2011; 131: 1300–1307.

    Article  CAS  PubMed  Google Scholar 

  83. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 2007; 13: 1757–1761.

    Article  CAS  PubMed  Google Scholar 

  84. Kang MJ, Kim KM, Bae JS, Park HS, Lee H, Chung MJ et al. Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma. Transl Oncol 2013; 6: 282–289.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE . The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 2013; 139: 667–676.

    Article  CAS  PubMed  Google Scholar 

  86. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N . Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002; 99: 12293–12297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003; 63: 6501–6505.

    CAS  PubMed  Google Scholar 

  88. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 2004; 64: 1140–1145.

    Article  CAS  PubMed  Google Scholar 

  89. Rosenwald A, Wright G, Leroy K, Yu X, Gaulard P, Gascoyne RD et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003; 198: 851–862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 2008; 111: 3220–3224.

    Article  CAS  PubMed  Google Scholar 

  91. Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 2003; 170: 1257–1266.

    Article  CAS  PubMed  Google Scholar 

  92. Xerri L, Chetaille B, Serriari N, Attias C, Guillaume Y, Arnoulet C et al. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol 2008; 39: 1050–1058.

    Article  CAS  PubMed  Google Scholar 

  93. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM . Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 2011; 17: 4232–4244.

    Article  CAS  PubMed  Google Scholar 

  94. Bentz M, Barth TF, Bruderlein S, Bock D, Schwerer MJ, Baudis M et al. Gain of chromosome arm 9p is characteristic of primary mediastinal B-cell lymphoma (MBL): comprehensive molecular cytogenetic analysis and presentation of a novel MBL cell line. Genes Chromosomes Cancer 2001; 30: 393–401.

    Article  CAS  PubMed  Google Scholar 

  95. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116: 3268–3277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood 2013; 121: 1367–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G et al. High numbers of tumor infiltrating FOXP3-positive regulatory T-cells are associated with improved overall survival in follicular lymphoma. Blood 2006; 108: 2957–2964.

    Article  CAS  PubMed  Google Scholar 

  98. Takahashi H, Tomita N, Sakata S, Tsuyama N, Hashimoto C, Ohshima R et al. Prognostic significance of programmed cell death-1-positive cells in follicular lymphoma patients may alter in the rituximab era. Eur J Haematol 2013; 90: 286–290.

    Article  CAS  PubMed  Google Scholar 

  99. Alvaro T, Lejeune M, Salvado MT, Lopez C, Jaen J, Bosch R et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol 2006; 24: 5350–5357.

    Article  PubMed  Google Scholar 

  100. Nunes C, Wong R, Mason M, Fegan C, Man S, Pepper C . Expansion of a CD8(+)PD-1(+) replicative senescence phenotype in early stage CLL patients is associated with inverted CD4:CD8 ratios and disease progression. Clin Cancer Res 2012; 18: 678–687.

    Article  CAS  PubMed  Google Scholar 

  101. Han Y, Wu J, Bi L, Xiong S, Gao S, Yin L et al. Malignant B cells induce the conversion of CD4+CD25- T cells to regulatory T cells in B-cell non-Hodgkin lymphoma. PLoS One 2011; 6: e28649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 2007; 110: 296–304.

    Article  CAS  PubMed  Google Scholar 

  103. Hallett WH, Jing W, Drobyski WR, Johnson BD . Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow Transplant 2011; 17: 1133–1145.

    Article  CAS  PubMed  Google Scholar 

  104. Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B et al. 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 2010; 116: 2286–2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kuranda K, Berthon C, Dupont C, Wolowiec D, Leleu X, Polakowska R et al. A subpopulation of malignant CD34+CD138+B7-H1+ plasma cells is present in multiple myeloma patients. Exp Hematol 2010; 38: 124–131.

    Article  CAS  PubMed  Google Scholar 

  106. Rosenblatt J, Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD et al. 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 2011; 34: 409–418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia 2013; 27: 464–472.

    Article  CAS  PubMed  Google Scholar 

  108. Feyler S, Scott GB, Parrish C, Jarmin S, Evans P, Short M et al. Tumour cell generation of inducible regulatory T-cells in multiple myeloma is contact-dependent and antigen-presenting cell-independent. PLoS One 2012; 7: e35981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98: 210–216.

    Article  CAS  PubMed  Google Scholar 

  110. Gorgun G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010; 116: 3227–3237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 2004; 103: 1787–1790.

    Article  CAS  PubMed  Google Scholar 

  112. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man HW, Schnetkamp PP et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther 2003; 305: 1222–1232.

    Article  CAS  PubMed  Google Scholar 

  113. Luptakova K, Rosenblatt J, Glotzbecker B, Mills H, Stroopinsky D, Kufe T et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol Immunother 2013; 62: 39–49.

    Article  CAS  PubMed  Google Scholar 

  114. Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 2009; 58: 1033–1045.

    Article  CAS  PubMed  Google Scholar 

  115. Idler I, Giannopoulos K, Zenz T, Bhattacharya N, Nothing M, Dohner H et al. Lenalidomide treatment of chronic lymphocytic leukaemia patients reduces regulatory T cells and induces Th17 T helper cells. Br J Haematol 2010; 148: 948–950.

    Article  CAS  PubMed  Google Scholar 

  116. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 2008; 14: 3044–3051.

    Article  CAS  PubMed  Google Scholar 

  117. Patnaik A, Kang AP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. J Clin Oncol 2012; 30 (Suppl): abstract 2515.

    Google Scholar 

  118. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28: 3167–3175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366: 2455–2465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369: 134–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res 2011; 71: 5111–5122.

    Article  CAS  PubMed  Google Scholar 

  123. Hobo W, Norde WJ, Schaap N, Fredrix H, Maas F, Schellens K et al. B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation. J Immunol 2012; 189: 39–49.

    Article  CAS  PubMed  Google Scholar 

  124. Ding ZC, Huang L, Blazar BR, Yagita H, Mellor AL, Munn DH et al. Polyfunctional CD4(+) T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood 2012; 120: 2229–2239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kearl TJ, Jing W, Gershan JA, Johnson BD . Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma. J Immunol 2013; 190: 5620–5628.

    Article  CAS  PubMed  Google Scholar 

  126. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA . Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res 2013; 19: 997–1008.

    Article  CAS  PubMed  Google Scholar 

  127. Robert C, Thomas L, Bondarenko I, O'Day S, M DJ, Garbe C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–2526.

    Article  CAS  PubMed  Google Scholar 

  128. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tarhini AA, Cherian J, Moschos SJ, Tawbi HA, Shuai Y, Gooding WE et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol 2012; 30: 322–328.

    Article  CAS  PubMed  Google Scholar 

  130. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G . Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 2013; 73: 3591–3603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol 2013; 190: 4899–4909.

    Article  CAS  PubMed  Google Scholar 

  133. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res 2012; 72: 5209–5218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. John LB, Devaud C, Duong CM, Yong C, Beavis PA, Haynes NM et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 2013; 19: 5636–5646.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology/Hematology/Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    D Atanackovic & T Luetkens

  2. Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    N Kröger

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  1. D Atanackovic
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Atanackovic, D., Luetkens, T. & Kröger, N. Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma. Leukemia 28, 993–1000 (2014). https://doi.org/10.1038/leu.2013.310

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