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:

The tumour microenvironment in B cell lymphomas

Key Points

  • B cell lymphomas show a range of extent and composition of tumour microenvironment components, partly reflecting tumour cell content and acquired genetic aberrations harboured by the lymphoma cells.

  • B cell lymphomas home to and co-opt the tumour microenvironment to derive survival and growth signals and to achieve escape from immune surveillance.

  • Tumour–microenvironment interactions are important contributors to both pathogenesis and prognosis of B cell lymphomas.

  • Some aspects of treatment resistance are mediated through tumour–microenvironment interactions, via factors secreted by stromal cells in response to lymphoma cells and cell adhesion-mediated drug resistance.

  • A fundamental understanding of tumour–microenvironment interactions underlies treatment strategies, including immune checkpoint blockade and separating lymphoma cells from their supportive microenvironment.

  • Future studies will include overlaying the genomic aberrations in the lymphoma cells on the composition of the tumour microenvironment and will aim to determine the functional consequences of these interactions.

Abstract

B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.

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

Access options

Buy this article

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

Figure 1: Composition of the B cell lymphoma microenvironment.
Figure 2: Survival and proliferation signals from the tumour microenvironment.
Figure 3: Interactions with the microenvironment that mediate immune escape.

Similar content being viewed by others

References

  1. Swerdlow, S. H. et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. (IARC Press, 2008).

    Google Scholar 

  2. Howlader N. et al. SEER Cancer Statistics Review, 1975–2010. National Cancer Institute. B ethesda, MD [online] (2013).

    Google Scholar 

  3. Canadian Cancer Society's Advisory Committee on Cancer Statistics. Canadian CancerStatistics, Toronto, ON. Canadian Cancer Society(2013).

  4. Shaffer, A. L. 3rd, Young, R. M. & Staudt, L. M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012). This is a state-of-art review of B cell lymphoma pathogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). This updated review highlights the emerging role of the tumour microenvironment in cancer biology.

    Article  CAS  PubMed  Google Scholar 

  6. Schmitz, R. et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490, 116–120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nature Med. 17, 983–988 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nature Med. 17, 975–982 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greaves, P. et al. Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells. Blood 122, 2856–2863 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Steidl, C., Connors, J. M. & Gascoyne, R. D. Molecular pathogenesis of Hodgkin's lymphoma: increasing evidence of the importance of the microenvironment. J. Clin. Oncol. 29, 1812–1826 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Pals, S. T., de Gorter, D. J. & Spaargaren, M. Lymphoma dissemination: the other face of lymphocyte homing. Blood 110, 3102–3111 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Lopez-Giral, S. et al. Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination. J. Leukoc. Biol. 76, 462–471 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Rehm, A. et al. Identification of a chemokine receptor profile characteristic for mediastinal large B-cell lymphoma. Int. J. Cancer 125, 2367–2374 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Rehm, A. et al. Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within secondary lymphoid organs. Blood 118, 1020–1033 (2011). This is an important animal model study demonstrating the importance of lymphoma cell homing to supportive microenvironments in disease establishment and progression.

    Article  CAS  PubMed  Google Scholar 

  16. Su, W., Spencer, J. & Wotherspoon, A. C. Relative distribution of tumour cells and reactive cells in follicular lymphoma. J. Pathol. 193, 498–504 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Oeschger, S., Bräuninger, A., Küppers, R. & Hansmann, M.-L. Tumor cell dissemination in follicular lymphoma. Blood 99, 2192–2198 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Schwickert, T. A., Alabyev, B., Manser, T. & Nussenzweig, M. C. Germinal center reutilization by newly activated B cells. J. Exp. Med. 206, 2907–2914 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, Z. Z., Novak, A. J., Ziesmer, S. C., Witzig, T. E. & Ansell, S. M. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood 110, 2537–2544 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ai, W. Z. et al. Follicular lymphoma B cells induce the conversion of conventional CD4+ T cells to T-regulatory cells. Int. J. Cancer 124, 239–244 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang, Z. Z., Novak, A. J., Ziesmer, S. C., Witzig, T. E. & Ansell, S. M. Malignant B cells skew the balance of regulatory T cells and TH17 cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 69, 5522–5530 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lens, S. M. A. et al. Aberrant expression and reverse signalling of CD70 on malignant B cells. Br. J. Haematol. 106, 491–503 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Yang, Z. Z., Novak, A. J., Stenson, M. J., Witzig, T. E. & Ansell, S. M. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 107, 3639–3646 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guilloton, F. et al. Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes. Blood 119, 2556–2567 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood 89, 3909–3918 (1997).

  26. Vega, F. et al. The stromal composition of malignant lymphoid aggregates in bone marrow: variations in architecture and phenotype in different B-cell tumours. Br. J. Haematol. 117, 569–576 (2002).

    Article  PubMed  Google Scholar 

  27. Rajnai, H. et al. Impact of the reactive microenvironment on the bone marrow involvement of follicular lymphoma. Histopathology 60, E66–E75 (2012).

    Article  PubMed  Google Scholar 

  28. Ghia, P., Granziero, L., Chilosi, M. & Caligaris-Cappio, F. Chronic B cell malignancies and bone marrow microenvironment. Semin. Cancer Biol. 12, 149–155 (2002).

    Article  PubMed  Google Scholar 

  29. Küppers, R. The biology of Hodgkin's lymphoma. Nature Rev. Cancer 9, 15–27 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Tweeddale, M. E. et al. The presence of clonogenic cells in high-grade malignant lymphoma: a prognostic factor. Blood 69, 1307–1314 (1987).

    CAS  PubMed  Google Scholar 

  31. Hussell, T., Isaacson, P. G., Crabtree, J. E. & Spencer, J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 342, 571–574 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Diehl, V. et al. Hodgkin's Disease: establishment and characterization of four in vitro cell lines. J. Cancer Res. Clin. 101, 111–124 (1981).

    Article  CAS  Google Scholar 

  33. Umetsu, D. T., Esserman, L., Donlon, T. A., DeKruyff, R. H. & Levy, R. Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. J. Immunol. 144, 2550–2557 (1990).

    CAS  PubMed  Google Scholar 

  34. Johnson, P. W. M. et al. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood 82, 1848–1857 (1993).

    CAS  PubMed  Google Scholar 

  35. Lam, K. P., Kühn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Kraus, M., Alimzhanov, M. B., Rajewsky, N. & Rajewsky, K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igα/β heterodimer. Cell 117, 787–800 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 5, 251–262 (2005).

    Article  CAS  Google Scholar 

  39. Raffeld, M., Neckers, L., Longo, D. L. & Cossman, J. Spontaneous alteration of idiotype in a monoclonal B-cell lymphoma - escape from detection by anti-idiotype. N. Engl. J. Med. 312, 1653–1658 (1985).

    Article  CAS  PubMed  Google Scholar 

  40. Meeker, T. et al. Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N. Engl. J. Med. 312, 1658–1665 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Sachen, K. L. et al. Self-antigen recognition by follicular lymphoma B cell receptors. Blood 120, 4182–4190 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cha, S. C. et al. Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen. J. Immunol. 190, 4887–4898 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Craig, V. J. et al. Gastric MALT lymphoma B cell express polyreactive, somatically mutated immunoglobulins. Blood 115, 581–591 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Bende, R. J. et al. Among B cell non-Hodgkin's lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J. Exp. Med. 201, 1229–1241 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hadzidimitriou, A. et al. Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases. Blood 118, 3088–3095 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Zhu, D. et al. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood 99, 2562–2568 (2002). This is the first description of N -glycosylation motifs as an acquired somatic event in FL that later implicated the tumour microenvironment in lymphoma pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  47. Coelho, V. et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc. Natl Acad. Sci. USA 107, 18587–18592 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McCann, K. J. et al. Remarkable selective glycosylation of the immunoglobulin variable region in follicular lymphoma. Mol. Immunol. 45, 1567–1572 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Roulland, S. et al. Early steps of follicular lymphoma pathogenesis. Adv. Immunol. 111, 1–46 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Stevenson, F. K. & Stevenson, G. T. Follicular lymphoma and the immune system: from pathogenesis to antibody therapy. Blood 119, 3659–3667 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88–92 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rossi, D. et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J. Exp. Med. 209, 1537–1551 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yan, Q. et al. BCR and TLR signaling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas. Haematologica 97, 595–598 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Treon, S. P. et al. MYD88 L265P somatic mutation in Waldenstrom's macroglobulinemia. N. Engl. J. Med. 367, 826–833 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, J. Q., Jeelall, Y. S., Beutler, B., Horikawa, K. & Goodnow, C. C. Consequences of the recurrent MYD88L265P somatic mutation for B cell tolerance. J. Exp. Med. 211, 413–426 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pangault, C. et al. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent TFH-B cell axis. Leukemia 24, 2080–2089 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Calvo, K. R. et al. IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma. Blood 112, 3818–3826 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Epron, G. et al. Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling. Leukemia 26, 139–148 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Belnoue, E. et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755–2764 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Munari, F. et al. Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma. Blood 117, 6612–6616 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Schwaller, J. et al. Paracrine promotion of tumor development by the TNF ligand APRIL in Hodgkin's disease. Leukemia 21, 1324–1327 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Schwaller, J. et al. Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness. Blood 109, 331–338 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Ogden, C. A. et al. Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: implications for Burkitt's lymphoma. J. Immunol. 174, 3015–3023 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Buske, C. et al. In vitro activation of low-grade non-Hodgkin's lymphoma by murine fibroblasts, IL-4, anti-CD40 antibodies and the soluble CD40 ligand. Leukemia 11, 1862–1867 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Lwin, T. et al. Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family in bone marrow stromal cells protects non-Hodgkin's B lymphoma cells from apoptosis. Leukemia 23, 170–177 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Amé-Thomas, P. et al. Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood 109, 693–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Medina, D. J. et al. Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor κB pathways. Haematologica 97, 1255–1263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dierks, C. et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nature Med. 13, 944–951 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Singh, R. R. et al. Hedgehog signaling pathway is activated in diffuse large B-cell lymphoma and contributes to tumor cell survival and proliferation. Leukemia 24, 1025–1036 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Kim, J. E. et al. Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma. Mod. Pathol. 22, 1312–1320 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Riemersma, S. A. et al. Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites. Blood 96, 3569–3577 (2000).

    CAS  PubMed  Google Scholar 

  76. Steidl, C. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wilkinson, S. T. et al. Partial plasma cell differentiation as a mechanism of lost major histocompatibility complex class II expression in diffuse large B-cell lymphoma. Blood 119, 1459–1467 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Rimsza, L. M. et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood 103, 4251–4258 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Challa-Malladi, M. et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell 20, 728–740 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nature Genet. 43, 830–837 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011). References 80 and 81, among others, established the landscape of recurrent mutations in DLBCL and revealed numerous mutations that influence tumour–microenvironment interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rosenwald, A. 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. 198, 851–862 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Steidl, C. et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 116, 418–427 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Diepstra, A. et al. HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin's lymphoma. Tissue Antigens 71, 219–226 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Verbeke, C. S., Wenthe, U., Grobholz, R. & Zentgraf, H. Fas ligand expression in Hodgkin lymphoma. Am. J. Surg. Pathol. 25, 388–394 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Ramsay, A. G. et al. Follicular lymphoma cell induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood 114, 4713–4720 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kiaii, S. et al. Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. J. Clin. Oncol. 31, 2654–2661 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang, Z. Z., Novak, A. J., Ziesmer, S. C., Witzig, T. E. & Ansell, S. M. Attenuation of CD8+ T-cell function by CD4+CD25+ regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res. 66, 10145–10152 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Amé-Thomas, P. et al. Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells. Leukemia 26, 1053–1063 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Sánchez-Aguilera, A. et al. Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma. Blood 108, 662–668 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Chetaille, B. et al. Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. Blood 113, 2765–2775 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Steidl, C. et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N. Engl. J. Med. 362, 875–885 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lenz, G. et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 359, 2313–2323 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. 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). References 94–96 highlight the role of the microenvironment in treatment outcome in B cell lymphomas.

    Article  CAS  PubMed  Google Scholar 

  97. Álvaro, T. et al. Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin. Cancer Res. 11, 1467–1473 (2005).

    Article  PubMed  Google Scholar 

  98. Kelley, T. W., Pohlman, B., Elson, P. & Hsi, E. D. The ratio of FOXP3+ regulatory T cells to granzyme B+ cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent of bcl-2 and MAL expression. Am. J. Clin. Pathol. 128, 958–965 (2007).

    Article  PubMed  Google Scholar 

  99. Bingle, L., Brown, N. J. & Lewis, C. E. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J. Pathol. 196, 254–265 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Fridman, W. H., Pagès, F., Sautès-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nature Rev. Cancer 12, 298–306 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Sánchez-Espiridión, B. et al. A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma. Blood 116, e12–e17 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Scott, D. W. et al. Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J. Clin. Oncol. 31, 692–700 (2013).

    Article  PubMed  Google Scholar 

  103. Meyer, P. N. et al. The stromal cell marker SPARC predicts for survival in patients with diffuse large B-cell lymphoma treated with rituximab. Am. J. Clin. Pathol. 135, 54–61 (2011).

    Article  PubMed  Google Scholar 

  104. Cardesa-Salzmann, T. M. et al. High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy. Haematologica 96, 996–1001 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. de Jong, D. et al. Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols. Haematologica 94, 70–77 (2009).

    Article  PubMed  Google Scholar 

  106. Gribben, J. G. Implications of the tumor microenvironment on survival and disease response in follicular lymphoma. Curr. Opin. Oncol. 22, 424–430 (2010).

    Article  PubMed  Google Scholar 

  107. Kridel, R., Sehn, L. H. & Gascoyne, R. D. Pathogenesis of follicular lymphoma. J. Clin. Invest. 122, 3424–3431 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sander, B. et al. The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium. Haematologica 99, 715–725 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Cerhan, J. R. et al. Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. Blood 109, 5439–5446 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Habermann, T. M. et al. Host immune gene polymorphisms in combination with clinical and demographic factors predict late survival in diffuse large B-cell lymphoma patients in the pre-rituximab era. Blood 112, 2694–2702 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ghesquieres, H. et al. Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: results from two independent cohorts. Cytokine 64, 523–531 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. McMillin, D. W., Negri, J. M. & Mitsiades, C. S. The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nature Rev. Drug Discov. 12, 217–228 (2013).

    Article  CAS  Google Scholar 

  113. Lwin, T. et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-κB (RelB/p52) in non-Hodgkin's lymphoma cells. Leukemia 21, 1521–1531 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Kurtova, A. V., Tamayo, A. T., Ford, R. J. & Burger, J. A. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood 113, 4604–4613 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mraz, M. et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-β-1 (VLA-4) with natalizumab can overcome this resistance. Br. J. Haematol. 155, 53–64 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lwin, T. et al. Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a. Blood 116, 5228–5236 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lwin, T. et al. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. J. Clin. Invest. 123, 4612–4626 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Lwin, T. et al. Cell adhesion induces p27 Kip 1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood 110, 1631–1638 (2007). References 116–118 describe the mechanisms by which direct interactions between lymphoma cells and stromal cells in the microenvironment lead to drug resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wotherspoon, A. C. et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342, 575–577 (1993). This paper, along with earlier papers showing the presence of H. pylori in gastric MALT lymphoma, established the link between pathogens in the microenvironment, the pathogenesis of MALT lymphoma and therapy.

    Article  CAS  PubMed  Google Scholar 

  120. Brody, J., Kohrt, H., Marabelle, A. & Levy, R. Active and passive immunotherapy for lymphoma: proving principles and improving results. J. Clin. Oncol. 29, 1864–1875 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Hegde, G. V. et al. Novel therapy for therapy-resistant mantle cell lymphoma: multipronged approach with targeting of hedgehog signaling. Int. J. Cancer 131, 2951–2960 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Advani, R. H. et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol. 31, 88–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Pallasch, C. P. et al. Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell 156, 590–602 (2014). This paper describes the use of autochthonous mouse models to investigate methods by which drug resistance associated with the tumour microenvironment may be overcome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. Ribatti, D., Nico, B., Ranieri, G., Specchia, G. & Vacca, A. The role of angiogenesis in human non-Hodgkin lymphomas. Neoplasia 15, 231–238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gratzinger, D. et al. Microvessel density and expression of vascular endothelial growth factor and its receptors in diffuse large B-cell lymphoma subtypes. Am. J. Pathol. 170, 1362–1369 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gratzinger, D. et al. Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy. Lab Invest. 88, 38–47 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Gratzinger, D. et al. Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R-CHOP). Br. J. Haematol. 148, 235–244 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Stopeck, A. T. et al. A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515. Blood 120, 1210–1217 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ruan, J. et al. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes. Blood 121, 5192–5202 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. O'Callaghan, K. et al. Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia. Blood 119, 1717–1725 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hu, Y. et al. Enhancement of the anti-tumor activity of therapeutic monoclonal antibodies by CXCR4 antagonists. Leuk. Lymphoma 53, 130–138 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Burger, J. A. & Montserrat, E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood 121, 1501–1509 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Chang, B. Y. et al. Egress of CD19+CD5+ cells into the peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients. Blood 122, 2412–2424 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genet. 46, 176–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep. 6, 130–140 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. von Andrian, U. H. & Mempel, T. R. Homing and cellular traffic in lymph nodes. Nature Rev. Immunol. 3, 867–878 (2003).

    Article  CAS  Google Scholar 

  139. Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nature Rev. Immunol. 9, 618–629 (2009).

    Article  CAS  Google Scholar 

  140. Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nature Rev. Immunol. 9, 15–27 (2009).

    Article  CAS  Google Scholar 

  141. McHeyzer-Williams, M., Okitsu, S., Wang, N. & McHeyzer-Williams, L. Molecular programming of B cell memory. Nature Rev. Immunol. 12, 24–34 (2012).

    Article  CAS  Google Scholar 

  142. Schwickert, T. A. et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208, 1243–1252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nature Immunol. 13, 1092–1100 (2012).

    Article  CAS  Google Scholar 

  144. Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nature Immunol. 13, 1083–1091 (2012).

    Article  CAS  Google Scholar 

  145. Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gitlin, A. D., Shulman, Z. & Nussenzweig, M. C. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943–952 (2004).

    Article  CAS  Google Scholar 

  148. Jares, P., Colomer, D. & Campo, E. Molecular pathogenesis of mantle cell lymphoma. J. Clin. Invest. 122, 3416–3423 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000). This paper describes using the similarity of gene expression profiles of lymphoma cells to a physiological counterpart to assign the cell of origin.

    Article  CAS  PubMed  Google Scholar 

  150. Victora, G. D. et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120, 2240–2248 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wotherspoon, A. C., Ortiz-Hidalgo, C., Falzon, M. R. & Isaacson, P. G. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338, 1175–1176 (1991).

    Article  CAS  PubMed  Google Scholar 

  152. Hussell, T., Isaacson, P. G., Crabtree, J. E. & Spencer, J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J. Pathol. 178, 122–127 (1996).

    Article  CAS  PubMed  Google Scholar 

  153. Isaacson, P. G. & Du, M.-Q. MALT lymphoma: from morphology to molecules. Nature Rev. Cancer 4, 644–653 (2004).

    Article  CAS  Google Scholar 

  154. Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhang, J. et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 110, 1398–1403 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Green, M. R. et al. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood 121, 1604–1611 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Bea, S. et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl Acad. Sci. USA 110, 18250–18255 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kiel, M. J. et al. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J. Exp. Med. 209, 1553–1565 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Richter, J. et al. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nature Genet. 44, 1316–1320 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Love, C. et al. The genetic landscape of mutations in Burkitt lymphoma. Nature Genet. 44, 1321–1325 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Dang, N. H. et al. Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J. Clin. Oncol. 22, 4095–4102 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Kuzel, T. M. et al. Phase II study of denileukin diftitox for previously treated indolent non-Hodgkin lymphoma: final results of E1497. Leuk. Lymphoma 48, 2397–2402 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Dang, N. H. et al. Phase II trial of the combination of denileukin diftitox and rituximab for relapsed/refractory B-cell non-Hodgkin lymphoma. Br. J. Haematol. 138, 502–505 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Ansell, S. M. et al. Denileukin diftitox in combination with rituximab for previously untreated follicular B-cell non-Hodgkin's lymphoma. Leukemia 26, 1046–1052 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Ansell, S. M. et al. Randomized phase II study of interleukin-12 in combination with rituximab in previously treated non-Hodgkin's lymphoma patients. Clin. Cancer Res. 12, 6056–6063 (2006).

    Article  CAS  PubMed  Google Scholar 

  166. Ansell, S. M. et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 15, 6446–6453 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bashey, A. et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood 113, 1581–1588 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. O'Mahony, D. et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin. Cancer Res. 13, 958–964 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. 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).

    Article  CAS  PubMed  Google Scholar 

  170. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 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).

    Article  CAS  PubMed  Google Scholar 

  172. Younes, A. et al. Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood 119, 4123–4128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Kasamon, Y. L. et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood 119, 4129–4132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ansell, S. M. et al. Phase I clinical study of atacicept in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma. Clin. Cancer Res. 14, 1105–1110 (2008).

    Article  CAS  PubMed  Google Scholar 

  175. Wiernik, P. H. et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J. Clin. Oncol. 26, 4952–4957 (2008).

    Article  PubMed  Google Scholar 

  176. Habermann, T. M. et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br. J. Haematol. 145, 344–349 (2009).

    Article  CAS  PubMed  Google Scholar 

  177. 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).

    Article  CAS  PubMed  Google Scholar 

  178. Witzig, T. E. et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann. Oncol. 22, 1622–1627 (2011).

    Article  CAS  PubMed  Google Scholar 

  179. Zinzani, P. L. et al. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann. Oncol. 24, 2892–2897 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Eve, H. E. et al. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br. J. Haematol. 159, 154–163 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Goy, A. et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J. Clin. Oncol. 31, 3688–3695 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Kiesewetter, B. et al. A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica 98, 353–356 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Fehniger, T. A. et al. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood 118, 5119–5125 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Zaja, F. et al. Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers. Haematologica 97, 416–422 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Wang, M. et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 13, 716–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Zinzani, P. L. et al. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin. Lymphoma Myeloma Leuk. 11, 462–466 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Wang, M. et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia 27, 1902–1909 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Ahmadi, T. et al. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer 120, 222–228 (2014).

    Article  CAS  PubMed  Google Scholar 

  189. Nowakowski, G. S. et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia 25, 1877–1881 (2011).

    Article  CAS  PubMed  Google Scholar 

  190. Tilly, H. et al. Phase Ib study of lenalidomide in combination with rituximab-CHOP (R2-CHOP) in patients with B-cell lymphoma. Leukemia 27, 252–255 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Chiappella, A. et al. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Haematologica 98, 1732–1738 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Stopeck, A. T. et al. A phase II trial of single agent bevacizumab in patients with relapsed, aggressive non-Hodgkin lymphoma: Southwest oncology group study S0108. Leuk. Lymphoma 50, 728–735 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Ruan, J. et al. Long-term follow-up of R-CHOP with bevacizumab as initial therapy for mantle cell lymphoma: clinical and correlative results. Clin. Lymphoma Myeloma Leuk. 14, 107–113 (2014).

    Article  PubMed  Google Scholar 

  194. Booman, M. et al. Mechanisms and effects of loss of human leukocyte antigen class II expression in immune-privileged site-associated B-cell lymphoma. Clin. Cancer Res. 12, 2698–2705 (2006).

    Article  CAS  PubMed  Google Scholar 

  195. Braggio, E. et al. Primary central nervous system lymphomas: a validation study of array-based comparative genomic hybridization in formalin-fixed paraffin-embedded tumor specimens. Clin. Cancer Res. 17, 4245–4253 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sung, C. O. et al. Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood 117, 1291–1300 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  198. Cheung, K. J. J. et al. High resolution analysis of follicular lymphoma genomes reveals somatic recurrent sites of copy-neutral loss of heterozygosity and copy number alterations that target single genes. Genes Chromosome Cancer 49, 669–681 (2010).

    Article  CAS  Google Scholar 

  199. Cheung, K. J. et al. Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res. 70, 9166–9174 (2010).

    Article  CAS  PubMed  Google Scholar 

  200. Morin, R. D. et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing. Blood 122, 1256–1265 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Green, J. A. et al. The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement. Nature Immunol. 12, 672–680 (2011).

    Article  CAS  Google Scholar 

  202. Cattoretti, G. et al. Targeted disruption of the S1P2 sphingosine 1-phosphate receptor gene leads to diffuse large B-cell lymphoma formation. Cancer Res. 69, 8686–8692 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Oricchio, E. et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147, 554–564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors receive research support from the Terry Fox Research Institute, Vancouver, Canada, the Canadian Institutes of Health Research, Genome Canada and Genome British Columbia and the Lymphoma Research Foundation US. The authors apologize to the numerous colleagues whose important contributions could not be included in this Review owing to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Randy D. Gascoyne.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Lymphoid structures

These include the primary lymphoid organs (bone marrow and thymus), secondary or peripheral lymphoid organs (lymph nodes, spleen and mucosa-associated lymphoid tissue) and the tertiary lymphoid organs, which develop at sites of infection and chronic stimulation of the immune system.

Sclerosis

A hardening or thickening of the tissue owing to excessive growth of fibrous connective tissue.

Reactive germinal centres

Physiological germinal centres that are produced in response to an antigenic stimulus.

Follicular dendritic cells

(FDCs). Stromal cells of mesenchymal origin that are located in the B cell follicles of secondary lymphoid organs, where they present intact antigen to B cells undergoing the germinal centre reaction, thereby contributing to affinity maturation.

Follicular T helper cells

(TFH cells). A distinct set of antigen-experienced CD4+ T helper cells that are focused in the germinal centre and contribute to the affinity maturation of B cells.

Hodgkin Reed–Sternberg cells

(HRS cells). The pathognomonic neoplastic B cells of classical Hodgkin's lymphoma with characteristic morphology, immunophenotype and genetic alterations, including classic binucleate cells (Reed–Sternberg cells) and mononuclear variants (Hodgkin cells).

Tingible-body macrophages

A type of macrophage that is found physiologically in germinal centres, with their appearance related to the staining characteristics of phagocytosed debris from apoptotic cells.

Follicular regulatory T cells

(TFR cells). A set of regulatory T cells that are CXC-chemokine receptor 5 (CXCR5)+ and BCL-6+, localized to germinal centres and prevent excessive germinal centre reactions.

Co-stimulation

Appropriate activation of T cells involves binding of the antigen by the T cell receptor, together with other 'co-stimulatory' signals from the cell presenting the antigen.

Tumour-associated macrophage

A cell derived from circulating monocytes or tissue-resident macrophages that is found in close proximity to tumours or within them.

Paratrabecular

Pertaining to being located adjacent to the trabeculae of bone in the bone marrow.

Fibroblastic reticular cells

(FRCs). Stromal cells that make up the scaffold of the T cell zone of secondary lymphoid organs; they direct lymphocyte trafficking within the organs and they present antigens.

Autochthonous animal models

Models in which the tumours arise in organs that are typically infiltrated by the cancer, potentially allowing the impact of interactions between the microenvironment of these organs and the tumour cells to be examined.

Anti-idiotype treatment

This treatment uses monoclonal antibodies that specifically recognize unique determinants in the variable regions of immunoglobulins on the tumour cells.

Somatic hypermutation

(SHM). This process is mediated by the enzyme activation-induced (cytidine) deaminase (AID), occurring in B cells in the germinal centres, whereby the variable regions of the immunoglobulin genes are mutated, allowing for an increased specificity of antibody for antigen.

Antigen-presenting cells

These cells, which include dendritic cells, macrophages and some B cells, mediate cellular immune responses by presenting antigen in the context of major histocompatibility complex class II to T cells.

Cytotoxic T lymphocytes

(CTLs). CD8+ T cells that kill cells on the basis of the presentation by that cell of specific antigen recognized by the T cell receptor of the cytotoxic T cell.

Natural killer cells

(NK cells). A type of cytotoxic lymphocyte (part of the innate immune system) that has a role in killing tumour cells and virally infected cells without the requirement for antigen presentation in the context of major histocompatibility complex class I.

Immune checkpoint blockade

A strategy that involves blockade of the inhibitory ligands and/or receptors that modify the response of T cells to antigen presented to the T cell receptor, thereby inhibiting T cell activation and impairing T cell function.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Scott, D., Gascoyne, R. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 14, 517–534 (2014). https://doi.org/10.1038/nrc3774

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3774

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