Lymphoma microenvironment: culprit or innocent?

Leukemia (2008) 22, 49–58 & 2008 Nature Publishing Group All rights reserved 0887-6924/08 $30.00 www.nature.com/leu REVIEW Lymphoma microenvironment: culprit or innocent? B Herreros, A Sanchez-Aguilera and MA Piris Lymphoma Group, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain Studies are revealing that lymphoid neoplasms are characterized by well-defined chromosome translocations and by the accumulation of subsequent molecular alterations involving mainly the cell cycle and/or apoptotic pathways. However, survival of B and T tumor cells is also dependent on the interactions with the accompanying cells that comprise the lymphoma microenvironment. Although non-tumor cells can contribute both positive and negative signals to the lymphoma cells, in this review we present compelling evidence of the essential influence of the tumor microenvironment on the initiation and progression of specific lymphoma types, highlighting some new therapeutic approaches that target the lymphoma microenvironment. Leukemia (2008) 22, 49–58; doi:10.1038/sj.leu.2404970; published online 4 October 2007 Keywords: lymphoma microenvironment; BCR signaling; BAFF/ APRIL; CD40; chemokines Introduction Tumor genesis and progression are driven by a combination of intrinsic eventsFoncogene activation and tumor-suppressor gene inactivation1Fand extrinsic events that are dependent on the interaction with the stroma. Multiple lines of evidence indicate that the lymphoma microenvironment plays an essential role in tumor origin. We will draw particular attention to some specific issues such as the development of lymphomas in sites usually lacking lymphocytes, as is the case for most of the extranodal lymphomas, the conspicuous presence of a complex cellular milieu that infiltrates some tumors, as is the rule in Hodgkin lymphoma (HL), and the case of the diffuse large B-cell lymphoma (DLBCL) variant known as Histiocyte/Tcell-rich Large B-cell Lymphoma (LBCL). Equally important is the demonstration that removing bacteria or viruses from the lymphoma microenvironment may stop lymphoma growth, with comparable effects to those obtained from chemotherapy.2–4 However, the role of the tumor microenvironment in initiating events in lymphoma development and tumor progression has not yet been studied in depth. The tumor microenvironment is composed of a dynamic and interactive mixture of cell subpopulations and cytokines, some of which have been only partially explored to date. Here, we review some of the most compelling evidence of a key role of the microenvironment in lymphoma pathogenesis (Table 1). Specific cell subpopulation components of the tumor microenvironment In recent years, a wide repertoire of new immune-cell subpopulations with characteristic cell-surface phenotypes, Correspondence: Dr MA Piris, Lymphoma Group, Molecular Pathology Program, Spanish National Cancer Center (CNIO), C/Melchor Fernández Almagro 3, Madrid 28029, Spain. E-mail: Received 7 May 2007; revised 24 August 2007; accepted 30 August 2007; published online 4 October 2007 gene-expression profiles and functions has been recognized. In this section, we will restrict ourselves to those cell subpopulations that are essential to explain the interactions between the tumor and its microenvironment, focusing on T cells, macrophages and dendritic cells (Table 2). Regulatory T cells Regulatory T (Treg) cells are a specific subset of T cells that have the capacity to inhibit effector immune responses mediated by CD4 and CD8 T cells, in order to restore immune homeostasis after antigen response and to suppress inappropriate immunoreactivity. Treg cells were initially characterized by the surface expression of CD25. However, this marker is also expressed in recently activated T cells, which have no suppressive capacity. Currently, the transcription factor FOXP3, a member of the forkhead family of DNA-binding transcription factors,42 has been generally accepted as being a definitive marker of Treg cells.27,43 Their development can be triggered by low-affinity antigen stimulation and seems to be dependent on cytokine signaling and to be independent of CD28. Treg cells can mediate their effects by producing immunosuppressive cytokines such as interleukin 10 (IL-10) or transforming growth factor-b (TGF-b), or by mechanisms involving direct interactions with responding T cells or antigen-presenting cells.28 The presence of Treg cells has been shown to be associated with different clinical outcomes, depending on their location, number and tumor context. Whereas they are associated with the induction of tumor tolerance in epithelial tumors, high numbers of Treg cells are a favorable trait in HL and follicular lymphoma (FL).9,14 Follicular B-helper T cells Follicular B-helper T (TFH) cells represent a heterogeneous population that differs from all other T-cell populations. It can be further divided into several subpopulations on the basis of the expression of different surface markers such as CD25, CD57, CD69 and CXCR5. It is still unclear whether TFH cells differentiate as a third, separate lineage at the time of T-cell priming, or whether they emerge at a later stage from nonpolarized, primed T cells, or even from polarized TH2 or TH1 cells. It has been convincingly shown that upon stimulation, TFH cells express OX14 (CD134), upregulate CD40L (CD154) and induce activation-induced cytidine deaminase expression in B cells, so that TFH cells promote germinal-center (GC) B-cell survival and differentiation, and allow immunoglobulin classswitching and somatic hypermutation.29 They also upregulate the expression of CXCR5, the receptor for CXCL13, a chemokine produced by follicular dendritic cells (FDCs) that promotes B cell entry into the GC and therefore facilitates B-cell–T-cell contacts. TFH cells are thought to represent the malignant population in angioimmunoblastic T-cell lymphoma (AITL).13 Macrophages Macrophages are part of the immune infiltrate found in a variety of lymphoma types. It has been shown in several experimental Lymphoma microenvironment B Herreros et al 50 Table 1 Lymphoma microenvironment Lymphoma type BCR stimulation Infection or autoimmunity Chemokines CD40/CD30 signaling Other relevant cell subpopulations Refs. CLL HL Yes No Autoantigen EBV infection CD40 CD30 T cells, NLC Mast cells, STAT1+ macrophages, eosinophils, CTL, Treg 5–8 AITL F CD30 TFH 13 FL Yes EBV infection, autoimmune process Autoantigen CXCL12 CXCL12 CXCL13 CCL19 CCL21 CXCL13 CD40 Yes (BCR cluster) F TRCBL SMZL F Yes F F F CD40 MALT Yes F Plasmodium, HCV H. pylori and others Treg, TFH, FDC, STAT1+ macrophages, stromal cells T and NK cells, macrophages, interdigitating dendritic cells, fibroblasts CTL, histiocytes T cells 14–17 DLBCL CXCL12 CXCL13 F F CD40 T cells 4 F 9–12 18,19 20,21 22–26 Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; BCR, B-cell receptor; (...truncated)