Skip to main content
SpringerLink
Log in

The follicular lymphoma microenvironment: From tumor cell to host immunity

  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Follicular lymphoma (FL) is a neoplasm derived from follicular germinal center cells. Like the normal components of this lymphoid structure, FL cells interact with various immune cells, such as the follicular helper T cells, suppressor regulatory T cells, dendritic cells, and histiocytes, that define the tumor microenvironment. Gene expression studies have shown that the nature of the tumor microenvironment predicts survival in patients with FL and may influence the response to immunotherapy and risk of transformation. The immune system may either promote or constrain tumor cell development, depending on the relative distribution and activation status of various cell subpopulations. The prognostic value of germline genetic variants of some immune genes suggests that the host genetic background may also influence the biology of FL. Some efforts have been carried out to validate those findings and provide clinical tools that may be used at the time of diagnosis.

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

Similar content being viewed by others

References and Recommended Reading

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

    Article  PubMed  Google Scholar 

  2. 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, 351:2159–2169.

    Article  PubMed  CAS  Google Scholar 

  3. Glas AM, Kersten MJ, Delahaye LJ, et al.: Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 2005, 105:301–307.

    Article  PubMed  CAS  Google Scholar 

  4. Glas AM, Knoops L, Delahaye L, et al.: Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. J Clin Oncol 2007, 25:390–398.

    Article  PubMed  CAS  Google Scholar 

  5. Husson H, Carideo EG, Neuberg D, et al.: Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays. Blood 2002, 99:282–289.

    Article  PubMed  CAS  Google Scholar 

  6. Sato E, Olson SH, Ahn J, et al.: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005, 102:18538–18543.

    Article  PubMed  CAS  Google Scholar 

  7. Galon J, Costes A, Sanchez-Cabo F, et al.: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313:1960–1964.

    Article  PubMed  CAS  Google Scholar 

  8. Rosenberg SA, Restifo NP, Yang JC, et al.: Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008, 8:299–308.

    Article  PubMed  CAS  Google Scholar 

  9. Schultze JL, Seamon MJ, Michalak S, et al.: Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma cells can be expanded in vitro. Blood 1997, 89:3806–3816.

    PubMed  CAS  Google Scholar 

  10. Farinha P, Gascoyne RD: Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005, 23:6370–6378.

    Article  PubMed  CAS  Google Scholar 

  11. Rohatiner AZ, Gregory WM, Peterson B, et al.: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 2005, 23:2215–2223.

    Article  PubMed  CAS  Google Scholar 

  12. 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, 106:2169–2174.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Byers RJ, Sakhinia E, Joseph P, et al.: Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling. Blood 2008, 111:4764–4770.

    Article  PubMed  CAS  Google Scholar 

  15. Alvaro T, Lejeune M, Camacho FI, et al.: The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. Haematologica 2006, 91:1605–1612.

    PubMed  CAS  Google Scholar 

  16. Jaffe ES, Shevach EM, Frank MM, et al.: Nodular lymphoma—evidence for origin from follicular B lymphocytes. N Engl J Med 1974, 290:813–819.

    PubMed  CAS  Google Scholar 

  17. Bende RJ, Smit LA, van Noesel CJ: Molecular pathways in follicular lymphoma. Leukemia 2007, 21:18–29.

    Article  PubMed  CAS  Google Scholar 

  18. Klein U, Dela-Favera R: Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008, 8:22–33.

    Article  PubMed  CAS  Google Scholar 

  19. Cong P, Raffeld M, Teruya-Feldstein J, et al.: In situ localization of follicular lymphoma: description and analysis by laser capture microdissection. Blood 2002, 99:3376–3382.

    Article  PubMed  CAS  Google Scholar 

  20. Gine E, Montoto S, Bosch F, et al.: The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 2006, 17:1539–1545.

    Article  PubMed  CAS  Google Scholar 

  21. Bohen SP, Troyanskaya OG, Alter O, et al.: Variation in gene expression patterns in follicular lymphoma and the response to rituximab. Proc Natl Acad Sci U S A 2003, 100:1926–1930.

    Article  PubMed  CAS  Google Scholar 

  22. Rademakers LH, Peters JP, van Unnik JA: Histiocytic and dendritic reticulum cells in follicular structures of follicular lymphoma and reactive hyperplasia. A quantitative electron microscopical analysis. Virchows Arch B Cell Pathol Incl Mol Pathol 1983, 44:85–98.

    Article  PubMed  CAS  Google Scholar 

  23. 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, 24:5350–5357.

    Article  PubMed  Google Scholar 

  24. Lee AM, Clear AJ, Calaminici M, et al.: Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. J Clin Oncol 2006, 24:5052–5059.

    Article  PubMed  CAS  Google Scholar 

  25. Banham AH, Powrie FM, Suri-Payer E: FOXP3+ regulatory T cells: current controversies and future perspectives. Eur J Immunol 2006, 36:2832–2836.

    Article  PubMed  CAS  Google Scholar 

  26. Lim HW, Hillsamer P, Kim CH: Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. J Clin Invest 2004, 114:1640–1649.

    PubMed  CAS  Google Scholar 

  27. Zhao D-M, Thornton AM, Dipaolo RJ, Shevach EM: Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 2006, 107:3925–3932.

    Article  PubMed  CAS  Google Scholar 

  28. King C, Tangye SG, Mackay CR: T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 2008, 26:741–766.

    Article  PubMed  CAS  Google Scholar 

  29. Haynes NM, Allen CD, Lesley R, et al.: Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1 high germinal center-associated subpopulation. J Immunol 2007, 179:5099–5108.

    PubMed  CAS  Google Scholar 

  30. Roncador G, García Verdes-Montenegro JF, Tedoldi S, et al.: Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica 2007, 92:1059–1066.

    Article  PubMed  CAS  Google Scholar 

  31. Canioni D, Salles G, Mounier N, et al.: High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol 2008, 26:440–446.

    Article  PubMed  CAS  Google Scholar 

  32. Mantovani A, Sica A, Locati M: New vistas on macrophage differentiation and activation. Eur J Immunol 2007, 37:14–16.

    Article  PubMed  CAS  Google Scholar 

  33. Shortman K, Liu YJ: Mouse and human dendritic cell subtypes. Nat Rev Immunol 2002, 2:151–161.

    Article  PubMed  CAS  Google Scholar 

  34. Park CS, Choi YS: How do follicular dendritic cells interact intimately with B cells in the germinal centre? Immunology 2005, 114:2–10.

    Article  PubMed  CAS  Google Scholar 

  35. Chang KC, Huang X, Medeiros LJ, Jones D: Germinal centre-like versus undifferentiated stromal immunophenotypes in follicular lymphoma. J Pathol 2003, 201:404–412.

    Article  PubMed  Google Scholar 

  36. Clayberger C, Luna-Fineman S, Lee JE, et al.: Interleukin 3 is a growth factor for human follicular B cell lymphoma. J Exp Med 1992, 175:371–376.

    Article  PubMed  CAS  Google Scholar 

  37. Peuchmaur M, Emilie D, Crevon MC, et al.: Interleukin-2 and interferon-gamma production in follicular lymphomas. Am J Clin Pathol 1991, 95:55–62.

    PubMed  CAS  Google Scholar 

  38. Fujii A, Oshima K, Hamasaki M, et al.: Differential expression of cytokines, chemokines and their receptors in follicular lymphoma and reactive follicular hyperplasia: assessment by complementary DNA microarray. Oncol Rep 2005, 13:819–824.

    PubMed  CAS  Google Scholar 

  39. Akamatsu N, Yamada Y, Hasegawa H, et al.: High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer Lett 2007, 256:196–206.

    Article  PubMed  CAS  Google Scholar 

  40. Martinez A, Pittaluga S, Rudelius M, et al.: Expression of the interferon regulatory factor 8/ICSBP-1 in human reactive lymphoid tissues and B-cell lymphomas: a novel germinal center marker. Am J Surg Pathol 2008, 32:1190–1200.

    Article  PubMed  Google Scholar 

  41. Karube K, Guo Y, Suzumiya J, et al.: CD10-MUM1+ follicular lymphoma lacks BCL2 gene translocation and shows characteristic biologic and clinical features. Blood 2007, 109:3076–3079.

    PubMed  CAS  Google Scholar 

  42. Cerhan JR, Ansell SM, Fredericksen ZS, et al.: Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood 2007, 110:4455–4463.

    Article  PubMed  CAS  Google Scholar 

  43. Nieters A, Beckmann L, Deeg E, Becker N: Gene polymorphisms in Toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk. Genes Immun 2006, 7:615–624.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Anatomic Pathology, Hospital Clinic, Villarroel 170, 08036, Barcelona, Spain

    Elias Campo

Authors
  1. Antonio Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joaquim Carreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elias Campo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elias Campo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martinez, A., Carreras, J. & Campo, E. The follicular lymphoma microenvironment: From tumor cell to host immunity. Curr Hematol Malig Rep 3, 179–186 (2008). https://doi.org/10.1007/s11899-008-0026-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-008-0026-6

Keywords

Search

Navigation