Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas

Key Points

  • A large percentage of patients with classic Hodgkin lymphoma (CHL), primary mediastinal B-cell lymphoma (PMBCL), primary testicular lymphoma, and primary central nervous system lymphoma have copy-number alterations and/or translocations involving the 9p24.1 locus

  • The 9p24.1 locus contains the genes encoding programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2), and JAK2; lymphoma-associated aberrations in this locus result in increased expression of these proteins

  • PD-L1 and/or PD-L2 induce immunosuppressive signalling via programmed cell-death protein 1 (PD-1); blockade of PD-1 with nivolumab results in response rates as high as 87% in patients with relapsed/refractory CHL

  • Nivolumab is currently approved by the FDA for the treatment of relapsed/refractory CHL, and many trials are underway to evaluate PD-1–PD-L1 blockade in patients with B-cell lymphomas

  • The PD-1–PD-L1 axis is probably important for immune evasion of B-cell lymphomas with a viral aetiology, specifically Epstein–Barr virus (EBV)-associated and human immunodeficiency virus (HIV)-associated lymphomas

  • PD-1 inhibition in diffuse large-B-cell lymphoma might be most effective when directed at specific disease subtypes, including PMBCL, T-cell/histiocyte-rich large-B-cell lymphoma, and EBV-positive disease

Abstract

Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1–PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1–PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed–Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV). This Review is focused on the role of PD-1–PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CTLA-4 and PD-1–PD-L1 immune checkpoints.

Similar content being viewed by others

References

  1. Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2105 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Atkins, M. B., Kunkel, L., Sznol, M. & Rosenberg, S. A. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am. 6, S11–14 (2000).

    PubMed  Google Scholar 

  3. Fisher, R. I., Rosenberg, S. A. & Fyfe, G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J. Sci. Am. 6, S55–S57 (2000).

    PubMed  Google Scholar 

  4. Rosenberg, S. A. et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271, 907–913 (1994).

    CAS  PubMed  Google Scholar 

  5. Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 183, 2541–2550 (1996).

    CAS  PubMed  Google Scholar 

  6. Freeman, G. J. 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. 192, 1027–1034 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Greaves, P. & Gribben, J. G. The role of B7 family molecules in hematologic malignancy. Blood 121, 734–744 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    PubMed  Google Scholar 

  10. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).

    CAS  PubMed  Google Scholar 

  11. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  Google Scholar 

  13. Weber, J. S. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015).

    CAS  PubMed  Google Scholar 

  14. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    PubMed  Google Scholar 

  18. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Patel, S. P. & Kurzrock, R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther. 14, 847–856 (2015).

    CAS  PubMed  Google Scholar 

  21. Roemer, M. G. et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J. Clin. Oncol. 34, 2690–2697 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shi, M. et al. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am. J. Surg. Pathol. 38, 1715–1723 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Chapuy, B. et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127, 869–881 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Carreras, J. et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J. Clin. Oncol. 27, 1470–1476 (2009).

    PubMed  Google Scholar 

  28. Richendollar, B. G., Pohlman, B., Elson, P. & Hsi, E. D. Follicular programmed death 1-positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma. Hum. Pathol. 42, 552–557 (2011).

    CAS  PubMed  Google Scholar 

  29. Sehn, L. H. et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J. Clin. Oncol. 23, 5027–5033 (2005).

    CAS  PubMed  Google Scholar 

  30. Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).

    CAS  PubMed  Google Scholar 

  31. Morton, L. M. et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood 107, 265–276 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Johnson, P. & McKenzie, H. How I treat advanced classical Hodgkin lymphoma. Blood 125, 1717–1723 (2015).

    CAS  PubMed  Google Scholar 

  33. Ng, A. K. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br. J. Haematol. 154, 23–31 (2011).

    PubMed  Google Scholar 

  34. Lavoie, J. C. et al. High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver. Blood 106, 1473–1478 (2005).

    CAS  PubMed  Google Scholar 

  35. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183–2189 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Chen, R. et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128, 1562–1566 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen, R. et al. Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood 119, 6379–6381 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Marshall, N. A. et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103, 1755–1762 (2004).

    CAS  PubMed  Google Scholar 

  39. Chemnitz, J. M. et al. RNA fingerprints provide direct evidence for the inhibitory role of TGFβ and PD-1 on CD4+ T cells in Hodgkin lymphoma. Blood 110, 3226–3233 (2007).

    CAS  PubMed  Google Scholar 

  40. Green, M. R. et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin. Cancer Res. 18, 1611–1618 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Green, M. R. 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 116, 3268–3277 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen, B. J. et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19, 3462–3473 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Yamamoto, R. et al. PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111, 3220–3224 (2008).

    CAS  PubMed  Google Scholar 

  44. Yamamoto, R. et al. B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Sci. 100, 2093–2100 (2009).

    CAS  PubMed  Google Scholar 

  45. Hao, Y. et al. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin. Cancer Res. 20, 2674–2683 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kozako, T. et al. PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 23, 375–382 (2009).

    CAS  PubMed  Google Scholar 

  47. Advani, R. H. et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte-predominant Hodgkin lymphoma. J. Clin. Oncol. 32, 912–918 (2014).

    CAS  PubMed  Google Scholar 

  48. Eichenauer, D. A. et al. Long-term course of patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. J. Clin. Oncol. 33, 2857–2862 (2015).

    CAS  PubMed  Google Scholar 

  49. Dorfman, D. M., Brown, J. A., Shahsafaei, A. & Freeman, G. J. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30, 802–810 (2006).

    PubMed  PubMed Central  Google Scholar 

  50. Armand, P. et al. PD-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: safety, efficacy, and biomarker assessment. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2016.67.3467 (2016).

  51. Chen, R. et al. Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087 study. J. Clin. Oncol. 34 (Suppl.), abstr. 7555 (2016).

    Google Scholar 

  52. Younes, A. et al. Checkmate 205: nivolumab (nivo) in classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV) — a phase 2 study. J. Clin Oncol. 34 (Suppl.), abstr. 7535 (2016).

    Google Scholar 

  53. US Food and Drug Administration. Nivolumab (Opdivo) for Hodgkin lymphoma. FDA http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm (2016).

  54. Tsimberidou, A.-M., Braiteh, F., Stewart, D. J. & Kurzrock, R. Ultimate fate of oncology drugs approved by the US Food and Drug Administration without a randomized trial. J. Clin. Oncol. 27, 6243–6250 (2009).

    CAS  PubMed  Google Scholar 

  55. Armand, P. et al. A phase 2 study of a nivolumab (nivo)-containing regimen in patients (pts) with newly diagnosed classical Hodgkin lymphoma (cHL): Study 205 Cohort D [abstract]. J. Clin. Oncol. 34 (Suppl.), TPS7573 (2016).

    Google Scholar 

  56. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02758717 (2016).

  57. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02581631 (2016).

  58. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01896999 (2016).

  59. Dunleavy, K. & Wilson, W. H. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood 125, 33–39 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Dunleavy, K. et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N. Engl. J. Med. 368, 1408–1416 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Savage, K. J. et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102, 3871–3879 (2003).

    CAS  PubMed  Google Scholar 

  62. Twa, D. D. W. et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123, 2062–2065 (2014).

    CAS  PubMed  Google Scholar 

  63. Chong, L. C. et al. Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 128, 1206–1213 (2016).

    CAS  PubMed  Google Scholar 

  64. Twa, D. D. W. & Steidl, C. Structural genomic alterations in primary mediastinal large B-cell lymphoma. Leuk. Lymphoma 56, 2239–2250 (2015).

    CAS  PubMed  Google Scholar 

  65. Yuan, J. et al. Identification of primary mediastinal large B-cell lymphoma at nonmediastinal sites by gene expression profiling: Am. J. Surg. Pathol. 39, 1322–1330 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Steidl, C. & Gascoyne, R. D. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood 118, 2659–2669 (2011).

    CAS  PubMed  Google Scholar 

  67. Weniger, M. A. et al. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein. Genes. Chromosomes Cancer 46, 406–415 (2007).

    CAS  PubMed  Google Scholar 

  68. Gowrishankar, K. et al. Inducible but not constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-κB. PLoS ONE http://dx.doi.org/10.1371/journal.pone.0123410 (2015).

  69. Lesokhin, A. M. et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J. Clin. Oncol. 34, 2698–2704 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02576990 (2016).

  71. Armitage, J. O. How I treat patients with diffuse large B-cell lymphoma. Blood 110, 29–36 (2007).

    CAS  PubMed  Google Scholar 

  72. Sehn, L. H. & Gascoyne, R. D. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 125, 22–32 (2015).

    CAS  PubMed  Google Scholar 

  73. Ziepert, M. et al. Standard International Prognostic Index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J. Clin. Oncol. 28, 2373–2380 (2010).

    CAS  PubMed  Google Scholar 

  74. Gisselbrecht, C. et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 28, 4184–4190 (2010).

    PubMed  PubMed Central  Google Scholar 

  75. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002).

    PubMed  Google Scholar 

  76. Shipp, M. A. et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat. Med. 8, 68–74 (2002).

    CAS  PubMed  Google Scholar 

  77. Andorsky, D. J. et al. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin. Cancer Res. 17, 4232–4244 (2011).

    CAS  PubMed  Google Scholar 

  78. Menter, T., Bodmer-Haecki, A., Dirnhofer, S. & Tzankov, A. Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. Hum. Pathol. 54, 17–24 (2016).

    CAS  PubMed  Google Scholar 

  79. Nicolae, A. et al. EBV-positive large B cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood 126, 863–872 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kiyasu, J. et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 126, 2193–2201 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Baumjohann, D., Baumjohann, D. & Ansel, K. M. Identification of T follicular helper (Tfh) cells by flow cytometry. Protoc. Exch. http://dx.doi.org/10.1038/protex.2013.060 (2013).

  82. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    CAS  PubMed  Google Scholar 

  83. Good-Jacobson, K. L. et al. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 11, 535–542 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kim, J. R. et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS ONE 8, e82870 (2013).

    PubMed  PubMed Central  Google Scholar 

  85. Thompson, R. H. 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. 13, 1757–1761 (2007).

    CAS  PubMed  Google Scholar 

  86. Ahearne, M. J. et al. Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma. Virchows Arch. 465, 351–358 (2014).

    CAS  PubMed  Google Scholar 

  87. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rossille, D. et al. High level of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse large B-cell lymphoma: results from a French multicenter clinical trial. Leukemia 28, 2367–2375 (2014).

    CAS  PubMed  Google Scholar 

  89. Berger, R. 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. 14, 3044–3051 (2008).

    CAS  PubMed  Google Scholar 

  90. Carroll, J. Anti-PD-1? Well, no, says Medivation as a partial hold forces a halt to 'pivotal' cancer study. FierceBiotech http://www.fiercebiotech.com/r-d/anti-pd-1-well-no-says-medivation-as-a-partial-hold-forces-a-halt-to-pivotal-cancer-study (2016).

  91. Armand, P. et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J. Clin. Oncol. 31, 4199–4206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Silverberg, M. J. & Abrams, D. I. AIDS-defining and non-AIDS-defining malignancies: cancer occurrence in the antiretroviral therapy era. Curr. Opin. Intern. Med. 6, 642–647 (2007).

    Google Scholar 

  93. Dunleavy, K. & Wilson, W. H. How I treat HIV-associated lymphoma. Blood 119, 3245–3255 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bower, M. How I treat HIV-associated multicentric Castleman disease. Blood 116, 4415–4421 (2010).

    CAS  PubMed  Google Scholar 

  95. Little, R. F. & Dunleavy, K. Update on the treatment of HIV-associated hematologic malignancies. Hematology Am. Soc. Hematol. Educ. Program 2013, 382–388 (2013).

    PubMed  Google Scholar 

  96. Olszewski, A. J., Fallah, J. & Castillo, J. J. Human immunodeficiency virus-associated lymphomas in the antiretroviral therapy era: analysis of the National Cancer Data Base. Cancer 122, 2689–2697 (2016).

    CAS  PubMed  Google Scholar 

  97. Sparano, J. A. et al. Opportunistic infection and immunologic function in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma treated with chemotherapy. J. Natl Cancer Inst. 89, 301–307 (1997).

    CAS  PubMed  Google Scholar 

  98. Chao, C. et al. History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis. Ann. Oncol. 25, 1821–1829 (2014).

    CAS  PubMed  Google Scholar 

  99. Carbone, A. et al. Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat. Rev. Clin. Oncol. 11, 223–238 (2014).

    CAS  PubMed  Google Scholar 

  100. Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

    CAS  PubMed  Google Scholar 

  101. Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    CAS  PubMed  Google Scholar 

  102. Shankar, P. et al. Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection. Blood 96, 3094–3101 (2000).

    CAS  PubMed  Google Scholar 

  103. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).

    CAS  PubMed  Google Scholar 

  104. Velu, V., Shetty, R. D., Larsson, M. & Shankar, E. M. Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options. Retrovirology 12, 14 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. Banga, R. et al. PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 22, 754–761 (2016).

    CAS  PubMed  Google Scholar 

  106. Cubas, R. A. et al. Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat. Med. 19, 494–499 (2013).

    CAS  PubMed  Google Scholar 

  107. Pillai, S. Love the one you're with: the HIV, B cell and TFH cell triangle. Nat. Med. 19, 401–402 (2013).

    CAS  PubMed  Google Scholar 

  108. Kahl, B. S. & Yang, D. T. Follicular lymphoma: evolving therapeutic strategies. Blood 127, 2055–2063 (2016).

    CAS  PubMed  Google Scholar 

  109. Korsmeyer, S. J. Bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80, 879–886 (1992).

    CAS  PubMed  Google Scholar 

  110. Salles, G. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377, 42–51 (2011).

    CAS  PubMed  Google Scholar 

  111. Witzig, T. E. et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's lymphoma. J. Clin. Oncol. 27, 5404–5409 (2009).

    CAS  PubMed  Google Scholar 

  112. Flinn, I. W. et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 123, 3406–3413 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. van Besien, K. et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 102, 3521–3529 (2003).

    CAS  PubMed  Google Scholar 

  114. de Jong, D. Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J. Clin. Oncol. 23, 6358–6363 (2005).

    CAS  PubMed  Google Scholar 

  115. Dave, S. S. et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N. Engl. J. Med. 351, 2159–2169 (2004).

    CAS  PubMed  Google Scholar 

  116. Smeltzer, J. P. et al. Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma. Clin. Cancer Res. 20, 2862–2872 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Myklebust, J. H. et al. High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood 121, 1367–1376 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Nakanishi, J. et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol. Immunother. 56, 1173–1182 (2006).

    PubMed  Google Scholar 

  119. Wu, C. et al. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 108, 19–24 (2006).

    PubMed  Google Scholar 

  120. Westin, J. R. et al. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol. 15, 69–77 (2014).

    CAS  PubMed  Google Scholar 

  121. Davis, T. A. et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J. Clin. Oncol. 18, 3135–3143 (2000).

    CAS  PubMed  Google Scholar 

  122. Frassanito, M. A., Cusmai, A. & Dammacco, F. Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin. Exp. Immunol. 125, 190–197 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hideshima, T., Bergsagel, P. L., Kuehl, W. M. & Anderson, K. C. Advances in biology of multiple myeloma: clinical applications. Blood 104, 607–618 (2004).

    CAS  PubMed  Google Scholar 

  124. Tamura, H. et al. Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia 27, 464–472 (2013).

    CAS  PubMed  Google Scholar 

  125. Liu, J. et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-γ and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 110, 296–304 (2007).

    CAS  PubMed  Google Scholar 

  126. Benson, D. M. 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 116, 2286–2294 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hallett, W. H. D., Jing, W., Drobyski, W. R. & Johnson, B. D. Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade. Biol. Blood Marrow Transplant. 17, 1133–1145 (2011).

    CAS  PubMed  Google Scholar 

  128. Iwai, Y. et al. 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 99, 12293–12297 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Kearl, T. J., Jing, W., Gershan, J. A. & Johnson, B. D. Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma. J. Immunol. 190, 5620–5628 (2013).

    CAS  PubMed  Google Scholar 

  130. Jungbluth, A. A. et al. The cancer-testis antigens CT7 (MAGE-C1) and MAGE-A3/6 are commonly expressed in multiple myeloma and correlate with plasma-cell proliferation. Blood 106, 167–174 (2005).

    CAS  PubMed  Google Scholar 

  131. Goodyear, O. et al. CD8+T cells specific for cancer germline gene antigens are found in many patients with multiple myeloma, and their frequency correlates with disease burden. Blood 106, 4217–4224 (2005).

    CAS  PubMed  Google Scholar 

  132. Alyea, E. et al. T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 98, 934–939 (2001).

    CAS  PubMed  Google Scholar 

  133. Lokhorst, H. M. et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N. Engl. J. Med. 373, 1207–1219 (2015).

    CAS  PubMed  Google Scholar 

  134. Krejcik, J. et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128, 384–394 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Luptakova, K. et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol. Immunother. 62, 39–49 (2013).

    CAS  PubMed  Google Scholar 

  136. US National Library of Medicine. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT02431208 (2016).

  137. Wilcox, R. A. et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 114, 2149–2158 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Marzec, M. et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl Acad. Sci. USA 105, 20852–20857 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Xerri, L. et al. Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum. Pathol. 39, 1050–1058 (2008).

    CAS  PubMed  Google Scholar 

  140. Han, L. et al. Role of programmed death ligands in effective T-cell interactions in extranodal natural killer/T-cell lymphoma. Oncol. Lett. 8, 1461–1469 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Kantekure, K. et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am. J. Dermatopathol. 34, 126–128 (2012).

    PubMed  PubMed Central  Google Scholar 

  142. Munir, S. et al. Cutaneous T cell lymphoma cells are targets for immune checkpoint ligand PD-L1-specific, cytotoxic T cells. Leukemia 27, 2251–2253 (2013).

    CAS  PubMed  Google Scholar 

  143. Miyoshi, H. et al. PD-L1 expression on neoplastic or stromal cell is respectively poor or good prognostic factor for adult T-cell leukemia/lymphoma. Blood 128, 1374–1381 (2016).

    CAS  PubMed  Google Scholar 

  144. Maloney, D. G. Graft-versus-lymphoma effect in various histologies of non-Hodgkin's lymphoma. Leuk. Lymphoma 44, S99–S105 (2003).

    PubMed  Google Scholar 

  145. Fenske, T. S. et al. Allogeneic hematopoietic cell transplantation as curative therapy for patients with non-Hodgkin lymphoma: increasingly successful application to older patients. Biol. Blood Marrow Transplant. 22, 1543–1551 (2016).

    PubMed  PubMed Central  Google Scholar 

  146. Pingali, S. & Champlin, R. Pushing the envelope — nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation. Bone Marrow Transplant. 50, 1157–1167 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Chang, X., Zang, X. & Xia, C.-Q. New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT. Bone Marrow Transplant. 51, 324–332 (2016).

    CAS  PubMed  Google Scholar 

  148. Deng, R. et al. B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease. J. Immunol. 194, 560–574 (2015).

    CAS  PubMed  Google Scholar 

  149. Blazar, B. R. et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism. J. Immunol. 171, 1272–1277 (2003).

    CAS  PubMed  Google Scholar 

  150. Blazar, B. R., Taylor, P. A., Panoskaltsis-Mortari, A., Sharpe, A. H. & Vallera, D. A. Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J. Immunol. 162, 6368–6377 (1999).

    CAS  PubMed  Google Scholar 

  151. Okiyama, N. & Katz, S. I. Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes. J. Autoimmun. 53, 1–9 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Davids, M. S. et al. Ipilimumab for patients with relapse after allogeneic transplantation. N. Engl. J. Med. 375, 143–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Straub, M. et al. CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity. Oncotarget 7, 12024–12034 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. Barrett, M. T. et al. Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. Oncotarget 6, 26483–26493 (2015).

    PubMed  PubMed Central  Google Scholar 

  155. Ikeda, S. et al. Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy. Genomic Med. 1, 16037 (2016).

    Google Scholar 

  156. Nanda, R., Chow, L. & Dees, E. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Cancer Res. 75 (Suppl.), abstr. S1-09 (2014).

    Google Scholar 

  157. Kataoka, K. et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 534, 402–406 (2016).

    CAS  PubMed  Google Scholar 

  158. Killock, D. Immunotherapy: study deciphers enigmatic mechanism of PD-L1 overexpression. Nat. Rev. Clin. Oncol. 13, 395–395 (2016).

    PubMed  Google Scholar 

  159. Bally, A. P., Austin, J. W. & Boss, J. M. Genetic and epigenetic regulation of PD-1 expression. J. Immunol. 196, 2431–2437 (2016).

    CAS  PubMed  Google Scholar 

  160. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Nakamura, N. et al. Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. Int. J. Hematol. 102, 327–334 (2015).

    CAS  PubMed  Google Scholar 

  162. Ju, W. et al. Augmented efficacy of brentuximab vedotin combined with ruxolitinib and/or navitoclax in a murine model of human Hodgkin's lymphoma. Proc. Natl Acad. Sci. USA 113, 1624–1629 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Sagiv-Barfi, I. et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl Acad. Sci. USA 112, E966–E972 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Dubovsky, J. A. et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122, 2539–2549 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Xia, Y., Jeffrey Medeiros, L. & Young, K. H. Signaling pathway and dysregulation of PD1 and its ligands in lymphoid malignancies. Biochim. Biophys. Acta 1865, 58–71 (2016).

    CAS  PubMed  Google Scholar 

  166. Care, M. A., Westhead, D. R. & Tooze, R. M. Gene expression meta-analysis reveals immune response convergence on the IFNγ–STAT1–IRF1 axis and adaptive immune resistance mechanisms in lymphoma. Genome Med. 7, 96 (2015).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of the authors is funded, in part, by the Joan and Irwin Jacobs Philanthropic Fund.

Author information

Authors and Affiliations

Authors

Contributions

A.G. researched the data for the article and wrote the manuscript. A.G. and R.K. provided substantial contributions to discussions of the content. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Aaron Goodman.

Ethics declarations

Competing interests

A.G. has received fellowship funding from Pfizer. S.P.P. has received research funding from Amgen, MedImmune, Pfizer, and Xcovery; consulting fees from Lilly; and speaking fees from Boehringer Ingelheim. R.K. has received research funds from Foundation Medicine, Genentech, Guardant, Merck Serono, Pfizer, and Sequenom; consultant fees from Sequenom; and has an ownership interest in CureMatch and Novena.

Supplementary information

Supplementary information S1 (table 1)

FDA-approved and investigational anti-PD-1 and anti-PD-L1 antibodies (PDF 154 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goodman, A., Patel, S. & Kurzrock, R. PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat Rev Clin Oncol 14, 203–220 (2017). https://doi.org/10.1038/nrclinonc.2016.168

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2016.168

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer