A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages

Purpose: The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors. Experimental Design: Seventy follicular lymphoma patients with extreme clinical outcome (“poor” and “good” cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in ≤5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used. Results: Independently of the Follicular Lymphoma International Prognostic Index, CD4+ cells were associated with poor outcome and programmed death-1–positive and CD8+ cells were associated with good outcome. The prognostic values of CD4+ and programmed death-1–positive cells were accentuated when they were follicular and that of CD8+ cells were accentuated when they were interfollicular. Follicular FOXP3+ cells were associated with good outcome and interfollicular CD68+ cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome. Conclusion: There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets. Clin Cancer Res; 16(2); 637–50.

[1]  L. Staudt,et al.  Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. , 2004, The New England journal of medicine.

[2]  T. Macdonald,et al.  IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes1 , 2007, The Journal of Immunology.

[3]  J. Timmerman,et al.  Interleukin-21: biology and application to cancer therapy. , 2008, Expert opinion on biological therapy.

[4]  Hervé Watier,et al.  From the bench to the bedside: ways to improve rituximab efficacy. , 2004, Blood.

[5]  J. Friedberg,et al.  Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a "vaccinal effect" of rituximab. , 2009, Blood.

[6]  Loise M. Francisco,et al.  PD-1 and its ligands in T-cell immunity. , 2007, Current opinion in immunology.

[7]  P. Solal-Céligny,et al.  Follicular lymphoma international prognostic index , 2006, Blood.

[8]  Karey Shumansky,et al.  Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). , 2005, Blood.

[9]  M. Karjalainen‐Lindsberg,et al.  Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and CHOP. , 2008, Blood.

[10]  K. Gupta,et al.  Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer , 2007, Nature Medicine.

[11]  G. Salles,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. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Emili Montserrat,et al.  High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. , 2006, Blood.

[13]  V. Bronte,et al.  Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells , 2008, Immunological reviews.

[14]  A. Chang,et al.  FOXP3 defines regulatory T cells in human tumor and autoimmune disease. , 2009, Cancer research.

[15]  B. Sander,et al.  CD8+ T-Cell Content in Diagnostic Lymph Nodes Measured by Flow Cytometry Is a Predictor of Survival in Follicular Lymphoma , 2007, Clinical Cancer Research.

[16]  S. Ansell,et al.  Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. , 2005, Blood.

[17]  T. Kelley,et al.  Biologic predictors in follicular lymphoma: Importance of markers of immune response , 2007, Leukemia & lymphoma.

[18]  S. Horning,et al.  The natural history of initially untreated low-grade non-Hodgkin's lymphomas. , 1984, The New England journal of medicine.

[19]  K. Tarte,et al.  Functional alteration of the lymphoma stromal cell niche by the cytokine context: role of indoleamine-2,3 dioxygenase. , 2009, Cancer research.

[20]  A. Banham,et al.  Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells1 , 2005, The Journal of Immunology.

[21]  A. López-Guillermo,et al.  High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  M. Karjalainen‐Lindsberg,et al.  A High Tumor-Associated Macrophage Content Predicts Favorable Outcome in Follicular Lymphoma Patients Treated with Rituximab and Cyclophosphamide-Doxorubicin-Vincristine-Prednisone , 2007, Clinical Cancer Research.

[23]  J. Radford,et al.  Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling. , 2008, Blood.

[24]  K. Makabe,et al.  High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. , 2007, Cancer letters.

[25]  T. Lister,et al.  Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  R. Stahel,et al.  T‐cell derived cytokines co‐stimulate proliferation of CD40‐activated germinal centre as well as follicular lymphoma cells , 1997, Hematological oncology.

[27]  M. Calaminici,et al.  Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  L. Esserman,et al.  Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. , 1990, Journal of immunology.

[29]  P. Hillsamer,et al.  Regulatory T cells can migrate to follicles upon T cell activation and suppress GC-Th cells and GC-Th cell-driven B cell responses. , 2004, The Journal of clinical investigation.

[30]  S. Krause,et al.  Ex Vivo-activated Human Macrophages Kill Chronic Lymphocytic Leukemia Cells in the Presence of Rituximab: Mechanism of Antibody-dependent Cellular Cytotoxicity and Impact of Human Serum , 2006, Journal of immunotherapy.

[31]  K. Tarte,et al.  CD40 Ligand Protects from TRAIL-Induced Apoptosis in Follicular Lymphomas through NF-κB Activation and Up-Regulation of c-FLIP and Bcl-xL1 , 2008, The Journal of Immunology.

[32]  W. Klapper,et al.  Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. , 2007, Haematologica.

[33]  K. Haas,et al.  The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy , 2004, The Journal of experimental medicine.

[34]  Marylène Lejeune,et al.  Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  C. Mackay,et al.  T follicular helper (TFH) cells in normal and dysregulated immune responses. , 2008, Annual review of immunology.

[36]  Daphne de Jong,et al.  Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols , 2009, Haematologica.

[37]  Peter Joosten,et al.  Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. , 2005, Blood.

[38]  Philip M Kluin,et al.  Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  C. Copie-Bergman,et al.  Peripheral T-cell Lymphomas With a Follicular Growth Pattern are Derived From Follicular Helper T Cells (TFH) and may Show Overlapping Features With Angioimmunoblastic T-cell Lymphomas , 2009, The American journal of surgical pathology.

[40]  S. Horning.  Follicular lymphoma, survival, and rituximab: is it time to declare victory? , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.