Skip to main content

Advertisement

SpringerLink
Log in

Targeting The Tumor Microenvironment in Lymphomas: Emerging Biological Insights and Therapeutic Strategies

  • Lymphomas (T Hilal, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review aims to discuss recent advances in elucidating the tumor microenvironment (TME) in B lymphomas and resultant novel therapeutic development.

Recent Findings

While tumor morphology, immunophenotype, and molecular profile are established factors that predict outcome and guide therapy, the prognostic impact of infiltrating, non-tumor cells is now emerging. This is simultaneously facilitating the development of new therapies that target non-tumor cells.

Summary

The tumor microenvironment (TME) is a complex ecosystem composed of infiltrating cells and byproducts, extracellular matrix, and other non-cellular tissues. In lymphomas, our current understanding of the role of the TME is principally informed by studies in B-cell lineage diseases. As we improve our understanding of lymphoma biology, the importance of the impact of the non-tumor cell microenvironment is becoming more apparent. This lays the foundation for the investigation and development of novel therapies and combination strategies that target non-tumor cells and tumor cell/non-tumor cell interactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14(8):517–34.

    Article  CAS  PubMed  Google Scholar 

  2. Fowler NH, Cheah CY, Gascoyne RD, et al. Role of the tumor microenvironment in mature B-cell lymphoid malignancies. Haematologica. 2016;101(5):531–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. de Leval L, Rickman DS, Thielen C, et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007;109(11):4952–63.

    Article  PubMed  CAS  Google Scholar 

  4. Swerdlow SHCE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th Edition). Lyon: IARC; 2017.

    Google Scholar 

  5. Plattel WJ, van den Berg A, Visser L, et al. Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin’s lymphoma. Haematologica. 2012;97(3):410–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hedvat CV, Jaffe ES, Qin J, et al. Macrophage-derived chemokine expression in classical Hodgkin’s lymphoma: application of tissue microarrays. Mod Pathol. 2001;14(12):1270–6.

    Article  CAS  PubMed  Google Scholar 

  7. Aldinucci D, Lorenzon D, Cattaruzza L, et al. Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. Int J Cancer. 2008;122(4):769–76.

    Article  CAS  PubMed  Google Scholar 

  8. Ma Y, Visser L, Roelofsen H, et al. Proteomics analysis of Hodgkin lymphoma: identification of new players involved in the cross-talk between HRS cells and infiltrating lymphocytes. Blood. 2008;111(4):2339–46.

    Article  CAS  PubMed  Google Scholar 

  9. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2002;99(12):4283–97.

    Article  CAS  PubMed  Google Scholar 

  10. • Hsi ED, Li H, Nixon AB, et al. Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study. Blood. 2019;133(16):1762–5 Cytokine imapct on the TME is well described, but this study shows how this cytokine signature can predict inferior clinical outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Greaves P, Clear A, Coutinho R, et al. Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. J Clin Oncol. 2013;31(2):256–62.

    Article  CAS  PubMed  Google Scholar 

  12. •• Jachimowicz RD, Pieper L, Reinke S, et al. Analysis of the tumor microenvironment by whole-slide image analysis identifies low B cell content as a predictor of adverse outcome in advanced-stage classical Hodgkin lymphoma treated with BEACOPP. Haematologica. 2020. Despite intensive, aggressive therapy with BEACOPP, there is a subset of patients with a specific TME signature that predicts inferior responsiveness.

  13. Alvaro T, Lejeune M, Salvadó MT, et al. Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005;11(4):1467–73.

    Article  PubMed  Google Scholar 

  14. Sánchez-Aguilera A, Montalbán C, de la Cueva P, et al. Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma. Blood. 2006;108(2):662–8.

    Article  PubMed  CAS  Google Scholar 

  15. Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362(10):875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tan KL, Scott DW, Hong F, et al. Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. Blood. 2012;120(16):3280–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guo B, Cen H, Tan X, Ke Q. Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma. BMC Med. 2016;14(1):159.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Klein JL, Nguyen TT, Bien-Willner GA, et al. CD163 immunohistochemistry is superior to CD68 in predicting outcome in classical Hodgkin lymphoma. Am J Clin Pathol. 2014;141(3):381–7.

    Article  PubMed  Google Scholar 

  19. • Gholiha AR, Hollander P, Hedstrom G, et al. High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms. Br J Haematol. 2019;184(2):192–201 B-cells, T-cells, macrophages, and other immune cells are well described prognostically in cHL, this study describes plasma cells as an important component, which is less well described in the literature.

    Article  CAS  PubMed  Google Scholar 

  20. Romano A, Parrinello NL, Vetro C, et al. Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up-front with a risk-adapted strategy. Br J Haematol. 2015;168(5):689–700.

    Article  CAS  PubMed  Google Scholar 

  21. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dunleavy K, Steidl C. Emerging biological insights and novel treatment strategies in primary mediastinal large B-cell lymphoma. Semin Hematol. 2015;52(2):119–25.

    Article  PubMed  Google Scholar 

  23. Cader FZ, Schackmann RCJ, Hu X, et al. Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell–rich and exhausted T-effector microenvironment. Blood. 2018;132(8):825–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Roberts RA, Wright G, Rosenwald AR, et al. Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood. 2006;108(1):311–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin’s lymphoma. Haematologica. 2008;93(2):193–200.

    Article  CAS  PubMed  Google Scholar 

  26. •• Armand P, Engert A, Younes A, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428–39 Literature that led to FDA approval of checkpoint inhibitors in cHL and PMBL, which target the TME in these diseases.

  27. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen R, Zinzani PL, Lee HJ, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood. 2019;134(14):1144–53 Literature that led to FDA approval of checkpoint inhibitors in cHL and PMBL, which target the TME in these diseases.undefined.

  29. •• Bröckelmann PJ, Goergen H, Keller U, et al. Efficacy of nivolumab and AVD in early-stage unfavorable classic Hodgkin lymphoma: the randomized phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol. 2020;6(6):872–80 Data supporting the investigation of moving checkpoint inhibitors into the frontline treatment of early stage, unfavorable, cHL.

    Article  PubMed  Google Scholar 

  30. •• Reinke S, Bröckelmann PJ, Iaccarino I, et al. Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1. Blood. 2020;136(25):2851–63 Checkpoint inhibitors are approved for use in HL, and this publication defines how a withdrawal of pro-survival factors, rather than a cytotoxic T-cell activation, is how these therapies affect the TME and attack the tumor.

    Article  PubMed  Google Scholar 

  31. •• Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol. 2019;37(34):3291–9 Literature that led to FDA approval of checkpoint inhibitors in cHL and PMBL, which target the TME in these diseases.

  32. Calabretta E, Carlo-Stella C. The many facets of CD38 in lymphoma: from tumor-microenvironment cell interactions to acquired resistance to immunotherapy. Cells. 2020;9(4).

  33. • Aoki T, Chong LC, Takata K, et al. Single-cell transcriptome analysis reveals disease-defining T-cell subsets in the tumor microenvironment of classic Hodgkin lymphoma. Cancer Discov. 2020;10(3):406–21 T-cells with LAG3 expression have been described within the TME of HL, which could suggest a target to improve immunotherapy in HL.

    Article  PubMed  Google Scholar 

  34. Janik JE, Morris JC, O'Mahony D, et al. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma. Proc Natl Acad Sci U S A. 2015;112(42):13045–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Horwitz SM, Hamadani M, Fanale MA, et al. Interim results from a phase 1 study of ADCT-301 (Camidanlumab Tesirine) show promising activity of a novel pyrrolobenzodiazepine-based antibody drug conjugate in relapsed/refractory Hodgkin/non-Hodgkin lymphoma. Blood. 2017;130(Supplement 1):1510–0.

    Google Scholar 

  36. Dunleavy K, Roschewski M, Wilson WH. Precision treatment of distinct molecular subtypes of diffuse large B-cell lymphoma: ascribing treatment based on the molecular phenotype. Clin Cancer Res. 2014;20(20):5182–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.

    Article  CAS  PubMed  Google Scholar 

  38. Chapuy B, Stewart C, Dunford AJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reddy A, Zhang J, Davis NS, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481–494.e415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lenz G, Wright G, Dave SS, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.

    Article  CAS  PubMed  Google Scholar 

  43. Riihijärvi S, Fiskvik I, Taskinen M, et al. Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial. Haematologica. 2015;100(2):238–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. • Ciavarella S, Vegliante MC, Fabbri M, et al. Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue. Ann Oncol. 2018;29(12):2363–70 Prior to this publication there was limited data on the prognostic impact of the TME in DLBCL. Myofibroblasts, dendritic cells, and CD4+ T-cells were all found to be associated with improved outcomes, whereas NK cells and plasma cells were associated with inferior outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hasselblom S, Sigurdadottir M, Hansson U, Nilsson-Ehle H, Ridell B, Andersson PO. The number of tumour-infiltrating TIA-1+ cytotoxic T cells but not FOXP3+ regulatory T cells predicts outcome in diffuse large B-cell lymphoma. Br J Haematol. 2007;137(4):364–73.

    Article  CAS  PubMed  Google Scholar 

  46. Challa-Malladi M, Lieu YK, Califano O, et al. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell. 2011;20(6):728–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kiyasu J, Miyoshi H, Hirata A, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015;126(19):2193–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. •• Griffin GK, Weirather JL, Roemer MGM, et al. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma. Blood. 2021;137(10):1353–64 This aggressive and difficult to treat subtype of DLBCL was found to have PD-L1 expressing TAMs and PD-1+ T cells, which argues for the use of immune checkpoint inhibitors in this disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chihara D, Dunleavy K. Primary central nervous system lymphoma: evolving biologic insights and recent therapeutic advances. Clin Lymphoma Myeloma Leuk. 2021;21(2):73–9.

    Article  PubMed  Google Scholar 

  50. Rubenstein JL. Biology of CNS lymphoma and the potential of novel agents. Hematology Am Soc Hematol Educ Program. 2017;2017(1):556–64.

    Article  PubMed  PubMed Central  Google Scholar 

  51. • Ponzoni M, Berger F, Chassagne-Clement C, et al. Reactive perivascular T-cell infiltrate predicts survival in primary central nervous system B-cell lymphomas. Br J Haematol. 2007;138(3):316–23 Describes insight into PCNSL TME, describing the presence of activated macrophages and reactive T-cells, and the prognostic impact of CXCL13.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br J Haematol. 2013;160(4):487–502.

    Article  CAS  PubMed  Google Scholar 

  53. Vitolo U, Chiappella A, Franceschetti S, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15(7):730–7.

    Article  CAS  PubMed  Google Scholar 

  54. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251–7.

    Article  CAS  PubMed  Google Scholar 

  55. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B-cell lymphoma in a randomized phase II US Intergroup Study ECOG-ACRIN E1412. J Clin Oncol. 2021;39(12):1329–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. •• Nowakowski GS, Chiappella A, Gascoyne RD, et al. ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma. J Clin Oncol. 2021;39(12):1317–28 Phase III clinical trial that unfortunately reported a lack of benefit for R2-CHOP vs R-CHOP, despite favorable results from earlier trials in ABC-type DLBCL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vitolo U, Trněný M, Belada D, et al. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017;35(31):3529–37.

    Article  CAS  PubMed  Google Scholar 

  58. Younes A, Sehn LH, Johnson P, et al. Randomized phase III Trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019;37(15):1285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wright GW, Huang DW, Phelan JD, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551–568.e514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ansell SM, Minnema MC, Johnson P, et al. Nivolumab for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for or having failed autologous transplantation: a single-arm, phase II study. J Clin Oncol. 2019;37(6):481–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. • Keane C, Law SC, Gould C, et al. LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Adv. 2020;4(7):1367–77 LAG3 expression in the DLBCL TME could help explain the poor responses noted with checkpoint inhibitors in the disease, and provide a new therapeutic avenue for clinical trials in the future.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Carpio C, Bouabdallah R, Ysebaert L, et al. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood. 2020;135(13):996–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Risueño A, Hagner PR, Towfic F, et al. Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent. Blood. 2020;135(13):1008–18 Avadomide, a novel therapeutic agent in DLBCL, was shown to produce clinical benefit in patients TME that displayed gene expression profiling rich in T-cell, macrophage, and immune/inflammatory signals.undefined.

  64. • Jain MD, Zhao H, Wang X, et al. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma. Blood. 2021;137(19):2621–33 High levels of monocytic myeloid derived suppressor cells, and high IL-6 and ferritin levels were associated with lack of durable CAR-T response in large B-cell lymphomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21(8):922–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sagiv-Barfi I, Kohrt HE, Czerwinski DK, Ng PP, Chang BY, Levy R. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A. 2015;112(9):E966–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lionakis MS, Dunleavy K, Roschewski M, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833–843 e835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ghesquieres H, Chevrier M, Laadhari M, et al. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol. 2019;30(4):621–8.

    Article  CAS  PubMed  Google Scholar 

  69. Nayak L, Iwamoto FM, LaCasce A, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129(23):3071–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bende RJ, Smit LA, van Noesel CJ. Molecular pathways in follicular lymphoma. Leukemia. 2007;21(1):18–29.

    Article  CAS  PubMed  Google Scholar 

  71. Alvaro T, Lejeune M, Salvadó MT, et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol. 2006;24(34):5350–7.

    Article  PubMed  Google Scholar 

  72. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351(21):2159–69.

    Article  CAS  PubMed  Google Scholar 

  73. Ramsay AG, Clear AJ, Kelly G, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood. 2015;125(1):40–7.

    Article  CAS  PubMed  Google Scholar 

  75. Farinha P, Masoudi H, Skinnider BF, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood. 2005;106(6):2169–74.

    Article  CAS  PubMed  Google Scholar 

  76. Farinha P, Al-Tourah A, Gill K, Klasa R, Connors JM, Gascoyne RD. The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood. 2010;115(2):289–95.

    Article  CAS  PubMed  Google Scholar 

  77. • Küppers R, Stevenson FK. Critical influences on the pathogenesis of follicular lymphoma. Blood. 2018;131(21):2297–306 Important discussion of the interactions between FL cells and TME cells, that lead to survival of tumor cells within the germinal center and BCR signaling.

    Article  PubMed  CAS  Google Scholar 

  78. Amin R, Mourcin F, Uhel F, et al. DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood. 2015;126(16):1911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. • Bararia D, Hildebrand JA, Stolz S, et al. Cathepsin S Alterations induce a tumor-promoting immune microenvironment in follicular lymphoma. Cell Rep. 2020;31(5):107522 Novel genetic alteration that is present in a subset of FL patients, which leads to activation of CD4+ T-cells, release of pro-inflammatory cytokines and growth of FL cells.

    Article  CAS  PubMed  Google Scholar 

  80. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164(6):811–21.

    Article  CAS  PubMed  Google Scholar 

  81. Henry JY, Labarthe MC, Meyer B, Dasgupta P, Dalgleish AG, Galustian C. Enhanced cross-priming of naive CD8+ T cells by dendritic cells treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide. Immunology. 2013;139(3):377–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lagrue K, Carisey A, Morgan DJ, Chopra R, Davis DM. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126(1):50–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. • Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188–99 Lenalidomide has a multi-mechanistic action on the TME, and the AUGMENT trial described clear PFS benefit for R2 vs rituximab in R/R FL, and it was found to have similar PFS compared to rituximab/chemotherapy in the upfront setting.

    Article  PubMed  PubMed Central  Google Scholar 

  84. • Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934–47 Lenalidomide has a multi-mechanistic action on the TME, and the AUGMENT trial described clear PFS benefit for R2 vs rituximab in R/R FL, and it was found to have similar PFS compared to rituximab/chemotherapy in the upfront setting.

    Article  CAS  PubMed  Google Scholar 

  85. Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018;36(23):2405–12.

    Article  CAS  PubMed  Google Scholar 

  86. Bartlett NL, Costello BA, LaPlant BR, et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2018;131(2):182–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sharman JP, Klein LM, Boxer M, et al. Phase 2 trial of entospletinib (GS-9973), a selective Syk inhibitor, in indolent non-Hodgkin’s lymphoma (iNHL). Washington, DC: American Society of Hematology; 2015.

    Book  Google Scholar 

  88. Barr PM, Saylors GB, Spurgeon SE, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127(20):2411–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. • Serrat N, Guerrero-Hernández M, Matas-Céspedes A, et al. PI3Kδ inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax. Blood Adv. 2020;4(17):4217–31 Investigators were able to show idelalisib exerted a general reshaping of the immune microenvironment (interference of CD40/CD40L pathway, downregulation of proteins critical for B-T-cell synapses, inefficient cross-talk between FL cells and T-follicular helpers) and restore cell dependence on BCL-2. This provides mechanistic rationale to combine venetoclax with PI3K inhibitors in FL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Palomero J, Vegliante MC, Rodríguez ML, et al. SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma. Blood. 2014;124(14):2235–47.

    Article  CAS  PubMed  Google Scholar 

  91. Balsas P, Palomero J, Eguileor Á, et al. SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma. Blood. 2017;130(4):501–13.

    Article  CAS  PubMed  Google Scholar 

  92. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113(19):4604–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Burger JA, Ford RJ. The microenvironment in mantle cell lymphoma: cellular and molecular pathways and emerging targeted therapies. Semin Cancer Biol. 2011;21(5):308–12.

    Article  CAS  PubMed  Google Scholar 

  94. Bernard S, Danglade D, Gardano L, et al. Inhibitors of BCR signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma. Int J Cancer. 2015;136(12):2761–74.

    Article  CAS  PubMed  Google Scholar 

  95. Rudelius M, Rosenfeldt MT, Leich E, et al. Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment. Haematologica. 2018;103(1):116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chiron D, Bellanger C, Papin A, et al. Rational targeted therapies to overcome microenvironment-dependent expansion of mantle cell lymphoma. Blood. 2016;128(24):2808–18.

    Article  CAS  PubMed  Google Scholar 

  97. Nygren L, Wasik AM, Baumgartner-Wennerholm S, et al. T-cell levels are prognostic in mantle cell lymphoma. Clin Cancer Res. 2014;20(23):6096–104.

    Article  CAS  PubMed  Google Scholar 

  98. Yang ZZ, Novak AJ, Stenson MJ, Witzig TE, Ansell SM. Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood. 2006;107(9):3639–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang L, Qian J, Lu Y, et al. Immune evasion of mantle cell lymphoma: expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells. Haematologica. 2013;98(9):1458–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015;126(6):739–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–67.

    Article  CAS  PubMed  Google Scholar 

  102. Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with zanubrutinib, a selective inhibitor of Bruton’s tyrosine kinase. Clin Cancer Res. 2020;26(16):4216–24.

    Article  CAS  PubMed  Google Scholar 

  103. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–23.

    Article  CAS  PubMed  Google Scholar 

  104. Dreyling M, Ladetto M, Doorduijn JK, et al. Triangle: autologous transplantation after a rituximab/ibrutinib/ara-c containing induction in generalized mantle cell lymphoma - a randomized European MCL Network Trial. Blood. 2019;134(Supplement_1):2816–6.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA

    Michael R. Cook & Kieron Dunleavy

Authors
  1. Michael R. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kieron Dunleavy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kieron Dunleavy.

Ethics declarations

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

Michael Cook declares no conflict of interest. Kieron Dunleavy has participated on advisory boards for Astra Zeneca, Beigene, Genmab, Abbvie, Morphosys, Daiichi Sankyo, Genentech and ADC Therapeutics.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Lymphomas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cook, M.R., Dunleavy, K. Targeting The Tumor Microenvironment in Lymphomas: Emerging Biological Insights and Therapeutic Strategies. Curr Oncol Rep 24, 1121–1131 (2022). https://doi.org/10.1007/s11912-022-01250-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-022-01250-y

Keywords

Search

Navigation