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The microenvironment in T-cell lymphomas: Emerging themes
Seminars in Cancer Biology, pages 49 - 60
Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by an aggressive clinical course and a mostly poor outcome with current treatment strategies. Despite novel insights into their pathobiology provided by recent genome-wide molecular studies, several entities remain poorly characterized. In addition to the neoplastic cell population, PTCLs have a microenvironment component, composed of non-tumor cells and stroma, which is quantitatively and qualitatively variable, and which may have an effect on their pathological and clinical features. The best example is provided by angioimmunoblastic T-cell lymphoma (AITL), a designation reflecting the typical vascularization and reactive immunoblastic content of the tumor tissues. In this disease, a complex network of interactions between the lymphoma cells and the microenvironment exists, presumably mediated by the neoplastic T cells with follicular helper T-cell properties. A better understanding of the crosstalk between neoplastic T or NK cells and their microenvironment may have important implications for guiding the development of novel therapies.
Keywords: T-cell lymphoma, Microenvironment, Angioimmunoblastic T-cell lymphoma, Folliclar helper T cell, Macrophages, Angiogenesis.
Peripheral T-cell lymphomas (PTCLs), which are neoplasms derived from mature T and NK cells, encompass numerous disease entities that collectively account for less than 15% of all non-Hodgkin lymphomas worldwide. Strikingly, their distribution shows important geographic variations, with a higher prevalence in Asia and central/south America than in Europe and North America, which is in part related to the endemic infection by the human T-lymphotropic virus-1 (HTLV1) and the Epstein–Barr virus (EBV)  . Most entities are clinically aggressive, with overall poor response to classical treatments and a dismal prognosis.
While the WHO principles of a multiparametric definition of lymphoma entities – based on morphologic, immunophenotypic, genetic and clinical features, and putative normal cellular counterpart – have led to a comprehensive delineation of B-cell lymphoma entities, the classification of NK/T-cell-derived neoplasms remains a challenge  . This difficulty is influenced by several factors, including the inherent complexity of the T-cell system, with its numerous functional subsets and probable functional plasticity. Additionally, PTCL entities comprise a broad range of morphologies and exhibit immunophenotypic profiles that tend to overlap across different entities. Only few recurrent genetic alterations have been described in PTCLs that can serve as disease-defining criteria. The clinical presentation, on the other hand, has been critical in defining PTCL entities. Recent findings indicate that the cell of origin is a major determinant of PTCL biology; nevertheless the cellular derivation of many PTCL entities remains poorly characterized or appears heterogeneous , , and .
There are currently more than 20 PTCL entities listed in the WHO classification; these can be grouped according to their presentation as disseminated (leukemic), predominantly extranodal or cutaneous, or predominantly nodal diseases ( Table 1 )  . Some entities are relatively well defined, while others are more heterogeneous, notably PTCL not otherwise specified (NOS), which is the “default” category for cases not fulfilling criteria for more specific entities. Some entities, for example ALK-negative anaplastic large cell lymphoma (ALCL) are provisional. ALK-positive ALCL is the only one defined by a genetic lesion, and is currently the best-defined entity.
|PTCL entities||Frequency (%) **||Cellular derivation||Phenotype|
|T-cell prolymphocytic leukemia||ND||Tαβ||Non-cytotoxic|
|T-cell large granular lymphocytic leukemia||ND||Tαβ (more rarely Tγδ)||Cytotoxic (A)|
|Chronic lymphoproliferative disorders of NK cells *||ND||NK||Cytotoxic (A)|
|Aggressive NK-cell leukemia||ND||NK||Cytotoxic (A)|
|Systemic EBV-positive T-cell lymphoproliferative disease of childhood||ND||Tαβ||Cytotoxic (A)|
|Adult T-cell leukemia/lymphoma||9.6||Tαβ||T regulatory|
|Extranodal NK/T-cell lymphoma, nasal type (ENKTCL)||10.4||NK (more rarely Tγδ or Tαβ)||Cytotoxic (A)|
|Enteropathy-associated T-cell lymphoma (EATL)||4.7||IEL, Tαβ (more rarely Tγδ)||Cytotoxic (A)|
|Hepatosplenic T-cell lymphoma (HSTL)||1.4||Tγδ (Vδ1) (more rarely Tαβ)||Cytotoxic (NA)|
|Mycosis fungoides||ND||Tαβ (mostly CD4)||Non-cytotoxic|
|Sézary syndrome||ND||Tαβ (mostly CD4)||Non-cytotoxic|
|Primary cutaneous CD30+ T-cell lymphoproliferative disorders||Tαβ (mostly CD4)|
|Primary cutaneous anaplastic large cell lymphoma||1.7||Tαβ (CD4)||Cytotoxic (A)|
|Lymphomatoid papulosis||ND||Tαβ (CD4)||Cytotoxic (A)|
|Subcutaneous panniculitis-like T-cell lymphoma||0.9||Tαβ (CD8)||Cytotoxic (A)|
|Primary cutaneous γδ T-cell lymphoma||ND||Tγδ (Vδ2)||Cytotoxic (A)|
|Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma *||ND||Tαβ (CD8)||Cytotoxic (A)|
|Primary cutaneous CD4+ small/medium T-cell lymphoma *||ND||Tαβ (CD4, TFH)||TFH|
|Hydroa vacciniforme-like lymphoma||ND||Tαβ (rarely NK)||Cytotoxic (A)|
|Peripheral T-cell lymphoma, not otherwise specified||25.9||Tαβ (CD4 > CD8), rarely Tγδ||Variable, a subset TFH, a subset cytotoxic (A)|
|Angioimmunoblastic T-cell lymphoma||18.5||Tαβ (CD4, TFH)||TFH|
|Anaplastic large-cell lymphoma, ALK-positive||6.6||Tαβ (likely Th2)||Cytotoxic (A)|
|Anaplastic large-cell lymphoma, ALK-negative *||5.5||Tαβ (Th2)||Cytotoxic (A)|
* Provisional entities.
** Statistics are based on pathologic anatomy registries, according to Armitage et al , with under-representation of leukaemic and cutaneous entities. ND, not determined
ALK, anaplastic lymphoma kinase; EBV, Epstein–Barr virus; NK, natural killer.
Cytotoxic (NA), non activated (expression of TIA-1 only); (A), activated (expression of perforin and/or granzyme B in addition to TIA-1).
It is remarkable that PTCL entities tend to have a predilection for development in specific anatomical sites, i.e. lymph nodes, skin, intestines, spleen and other extranodal organs. Accordingly, at the molecular level, distinct extranodal PTCL entities have a gene expression signature component that is organ-specific  and . For some entities, the association reflects derivation from a subset of organ-specific lymphocytes, or lymphocytes with peculiar homing properties. For example, enteropathy-associated T-cell lymphoma (EATL) which typically presents as a single or multiple jejunal lesion(s), is derived from intraepithelial lymphocytes of the intestinal mucosa. Most cases of hepatosplenic T-cell lymphoma (HSTL) are thought to derive from functionally immature cytotoxic γδ T cells of the splenic pool with vδ1 gene usage. Epidermotropic mycosis fungoides (MF), which is the most common cutaneous lymphoma, is associated with an expansion of lymphoid cells with homing properties to the skin. Altogether, this suggests the importance of tissue-specific factors in sustaining or promoting tumor growth. Interestingly, a feature common to extranodal PTCL entities is the rarity of dissemination to the bone marrow and the lymph nodes.
In addition to the neoplastic cell population PTCLs have a microenvironment component, composed of non-tumor cells and stroma, which may exhibit quantitative and qualitative variance ( Fig. 1 ). In certain PTCL entities, the non-neoplastic component is itself a defining feature. For example, in angioimmunoblastic T-cell lymphoma (AITL), the typical vascularization and immunoblastic content of the tumor tissues are among the defining criteria of the disease ( Fig. 2 A). Other examples include the follicular variant of PTCL, NOS, which is named after a growth pattern of the lymphoma cells in association with follicles and follicular dendritic cells; and the lymphoepithelioid variant (Lennert's lymphoma) defined by the presence of an abundant histiocytic infiltrate ( Fig. 1 A). In PTCL, NOS and in ALK-positive ALCL in particular, the microenvironment component can vary significantly in individual cases, and in some instances, the abundance of the non-neoplastic component may obscure the neoplastic cell population ( Fig. 1 B and 1C).
The characterization of the microenvironment in PTCL remains largely unexplored and the functional interactions between the microenvironment and neoplastic components poorly understood. In this section we will focus our review on AITL, emphasize the potential contribution of the germinal center milieu to T-cell lymphomagenesis and summarize the literature on distinct environmental components in other PTCL subtypes.
2. Microenvironment in T-cell lymphomas: the paradigm of angioimmunoblastic T-cell lymphoma
2.1. From angioimmunoblastic lymphadenopathy to lymphoma
AITL, originally described in the 1970s as “angioimmunoblastic lymphadenopathy (AILD) with dysproteinemia”  , “immunoblastic lymphadenopathy”  or “lymphogranulomatosis X”  , was initially reported as a nonneoplastic lymphoproliferation and believed to represent an abnormal “hyperimmune” reaction of the B-cell system or an atypical lymphoid process, despite a clinical course characterized by multiple relapses and a fatal outcome in the majority of patients  . The successive designations of the disease referring to immunoblasts, granulomatous infiltrate and angiogenesis underlined the importance of the microenvironment in disease definition. Subsequently, the identification of morphologic features of malignancy in cases with features of AILD led to the designation “immunoblastic T-cell lymphoma”  . In the 1980s, the discovery of clonal cytogenetic abnormalities and of clonal T-cell receptor (TCR) gene rearrangements definitively established the neoplastic nature of the disease , , , and .
AITL was since recognized as one of the most common forms of PTCL in the REAL and WHO classifications of hematologic malignancies , , and . According to the data of the international T-cell lymphoma project, AITL is the second most common form of PTCL, accounting for 18.5% of the cases worldwide. Interestingly, the disease is more common in Europe (representing 29% of the cases) than in North America or Asia where its prevalence is estimated to be 16% and 18% of the cases, respectively  and . According to a recent survey of the French National Lymphoma network (Lymphopath), since 2010, AITL accounts for around one third of non-cutaneous PTCLs and thus represents the most prevalent entity  . The heterogeneous geographic distribution might in part be explained by the overall low prevalence of T-cell neoplasms in Western countries and a relative overrepresentation of other NK/T-cell lymphoma types in Asia, but true differences might exist. In spite of this, no risk factors or etiologic agent(s) have been identified, and no racial predisposition has been recognized.
2.2. Distinctive clinical and biological features of AITL
AITL usually affects elderly adults, at a median age around 60 years  and . AITL is unique among lymphomas in terms of its peculiar clinical features. The disease is characterized by generalized lymphadenopathy, often accompanied by constitutional symptoms such as fever and weight loss. Extranodal manifestations are common, especially skin lesions, bone marrow involvement, hepatomegaly and splenomegaly, indicating that the neoplastic cells can spread from the lymph nodes and can develop an appropriate niche for their maintenance or cell growth in many different tissues. The disease is diagnosed at stage III or IV in more than 80% of cases. Conventional chemotherapy regimens are typically ineffective and the disease is considered incurable. The median survival is less than three years in most studies, but a subset of patients exhibit long-term survival  and .
Laboratory tests often disclose a variety of abnormalities at diagnosis including anemia (often hemolytic and Coombs-positive), polyclonal hypergammaglobulinemia and hypereosinophilia. Although lymphocytosis is rare, flow cytometry disclose presence of a variable percentage of cells with an aberrant cell surface immunophenotype (most commonly CD10+, ICOS+ and/or sCD3- or dim), therefore reflecting subtle blood dissemination  and . Other common findings include lymphopenia and the presence of various autoantibodies (e.g. rheumatoid factor, anti-nuclear factor, anti-smooth muscle), indicating B-cell immunological activation.
2.3. Crosstalk between neoplastic TFH cells and their microenvironment
Characteristic AITL histopathologic features include prominent arborizing high endothelial venules, irregular perivascular proliferation of follicular dendritic cells (FDCs) in close contact with neoplastic cells and vessels, and a polymorphic cellular infiltrate ( Fig. 2 A and B). The lymphoproliferation is typically diffuse (referred to as pattern III), while other patterns (with hyperplastic follicle, pattern I, and with depleted follicles, pattern II) are less common  and .
A major advance in the understanding of the pathophysiology of AITL was the discovery of the cellular derivation of AITL from T follicular helper (TFH) cells, which was initially suspected on the basis of expression of single TFH markers in AITL tumor cells, particularly the CXCL13 chemokine , , , and , and which was further validated at the molecular level by analysis of genome-wide transcriptional signatures  and . TFH cells represent a distinct functional subset of effector T helper (Th) cells , , and . TFH cells reside in germinal centers (GC) where their interaction with GC B cells is critical in promoting B-cell survival, Ig class-switch recombination and somatic hypermutation, ultimately yielding high-affinity plasma cells and memory B cells (for review, see Ref.  ). TFH differentiation is dependent upon the transcriptional repressor BCL6. TFH cell functions correlate with a specific secretory profile, including the expression of IL-21 and CXCL13 chemokines critical for B-cell recruitment into GCs and subsequent activation. TFH cells also have a characteristic cell surface immunophenotype that includes CXCR5, which is the CXCL13 receptor, and which is essential to TFH localization to GCs; as well as a variety of co-stimulatory molecules such as PD1, CD200, ICOS, and CD40L which favor strong interactions with B cells and consequently B-cell responses ( Table 2 ).
|TFH marker||Type of molecule||Function|
|CXCR5||Cell surface molecule, chemokine receptor||Receptor for the CXCL13 chemokine, essential for entry into the GC|
|CXCL13||Chemokine||Ligand of CXCR5, recruitment of CXCR5-positive B cells and T cells into GC|
|PD-1||Cell surface protein, member of the CD28 costimulatory receptor family||Receptor of PD-1-Ligands, negative regulator of T-cell activation|
|(CD279, PDCD1)||Cell death, T cell proliferation|
|Role in autoimmunity|
|ICOS||Cell surface protein, member of the CD28 costimulatory receptor||Favors T-cell proliferation and production of cytokines (IL-4 and IL-10)|
|SAP||Adaptator molecule, T-cell signal transduction||Binds to receptors of the signaling lymphocyte-activation molecule (SLAM and CD150) family expressed in cells of the immune system; plays a role in the terminal differentiation of TFH cells and induces bidirectional stimulation of T (TFH) and B (GC) cells|
|CD200||Immunoglobulin superfamily membrane protein (OX-2 membrane glycoprotein)||Binding to CD200R, an Ig superfamily inhibitory receptor on myeloid/monocytic lineage cells leads to a suppressive effect on T-cell-mediated immune responses|
|BCL-6||Nuclear transcription repressor||Master regulator of TFH differentiation|
|c-MAF||Nuclear transcription factor||Regulation of transcription, specific for TFH cells|
|IL-21||Cytokine||Control of germinal center B-cell differentiation, critical component of the memory B cell response; autocrine effect on T cells for optimal TFH differentiation|
AITL lymphoma cells are small to medium-sized mature αβ CD4+CD8-T-cells ( Fig. 2 A). Consistent with their TFH cellular derivation, they express several TFH-associated antigens such as PD1, ICOS, BCL6, CXCL13, SAP, CD200, and c-MAF, which are relevant for the diagnosis in clinical practice  and . In the majority of cases, coexpression of the neutral endopeptidase CD10 is observed in a variable proportion of the neoplastic cells , , , and . Collectively, CD10 and TFH markers highlight the nature of the neoplastic component while underscoring in parallel the non-neoplastic component of reactive CD4+ T lymphocytes and more notably, of CD8+ cytotoxic T lymphocytes (TIA1+, Granzyme B+). The CD8+ component can comprise a significant subpopulation and can exhibit features of activated cells with larger nuclei  .
The cellular derivation of AITL from TFH cells provides a rational model to explain the formation of the characteristic AITL microenvironment and the origin of several peculiar features inherent to this disease ( Fig. 3 )  . Indeed in AITL, the neoplastic cells are often outnumbered by the admixed polymorphous reactive infiltrate, and may be difficult to identify. Clinically, the manifestations of the disease mostly reflect a deregulated immune and/or inflammatory response rather than direct complications of tumor growth, supporting the concept of paraneoplastic immunological dysfunction. By molecular profiling, the AITL gene expression signature is dominated by a strong microenvironment imprint, including overexpression of B-cell- and FDC-related genes including immunoglobulins and clusterins; chemokines and chemokine receptors (CCL19, CCL20, CCL22, CCL24, IL4); and genes related to extracellular matrix (including several collagens and a number of matrix metallopeptidases) and vascular biology (such as VEGF, thrombomodulin, angiopietin 2)  .
Large B-cell blasts, often infected by EBV, and often distributed across the tissues are present in a large majority of the cases ( Fig. 2 C). Plasma cells, often polytypic, are present in variable number. In some instances, they can obscure the neoplastic component and some AITL patients even present peripheral blood polyclonal plasmacytosis, which mimicks plasma cell leukemia , , and . Interactions by contact are likely to occur between TFH cells and B cells, with neoplastic T-cell rosettes often seen around B-cell blasts. These interactions are mediated by ligand-receptor pairs expressed on the membrane (such as ICOS-ICOS-L and CD40-CD40L) ( Fig. 2 D). TFH cells are also able to secrete various soluble factors that are likely to be involved in promoting recruitment, activation and differentiation of other cellular subsets, and that could act as autocrine factors. CXCL13 is probably a major molecular mediator secreted by neoplastic TFH cells that can promote B-cell expansion and plasmacytic differentiation, which are ultimately responsible for the common AITL dysimmune manifestations, especially hypergammaglobulinemia and Coombs-positive hemolytic anemia. Plasmacytic proliferation is also promoted by other cytokines such as mast cell- and neoplastic TFH cell-produced interleukin-6  . Interestingly, in an experimental model, AITL cells were shown to increase antibody production by B cells or plasma cells  . IL-21 is another soluble factor secreted by TFH cells that exhibits an autocrine effect on the IL-21+ TFH, and that exerts positive effects on B cells.
Lymphotoxin beta, which is potentially released by B cells under CXCL13 stimulation, is expressed in AITL tumor cells  and might be involved in inducing FDC proliferation. Interestingly, the FDCs can show discordant expression of FDC markers such as CD21 and CD23, with a frequent loss of CD23 reported; however, this is not linked to an increased risk of FDC neoplasms. Upregulation of several angiogenic mediators has also been demonstrated in AITL. Vascular endothelial growth factor (VEGF) is overexpressed in AITL and probably acts as a key mediator of the prominent vascularization observed in the disease  and . By immunostaining, neoplastic cells and endothelial cells are positive for both VEGF and its receptor, suggesting the possibility of some paracrine and/or autocrine loop  and . Moreover, FDC and mast cells may sustain angiogenesis as they represent other sources of VEGF  and . The angiopoietin system may also play an important role as angiopoietin 1 is expressed by AITL neoplastic cells and FDCs  .
Eosinophils are almost always present in AITL tissues, although in variable numbers. Blood hypereosinophilia is seen in 30–50% of AITL patients at diagnosis  , and bone marrow hyperplasia with eosinophilia is common. Eosinophilic infiltrate in tumor biopsies correlate with CCL17/TARC mRNA expression by tumor-infiltrating mononuclear cells, and with IL-5 expression by the neoplastic cells, but not with CCL11/eotaxin-1  . Increased expression of IL-4, IL-5, and IL-13 has been demonstrated in CD3+ T-cells isolated from AITL lymph nodes compared to other lymphoma types, and these cytokines are potential mediators of eosinophilia  . Whether increased eosinophilopoiesis is favored by tumor cells themselves, or by tumor-infiltrating reactive Th2 cells attracted by locally produced CCL17/TARC, remains unclear. Eosinophilia does not appear to have an impact on AITL prognosis  .
AITL also comprises a variable amount of macrophages, and a subset of cases characterized by a high content of epithelioid cells in clusters (epithelioid variant of AITL) raise differential diagnosis issues, as they can be mistaken for a granulomatous disease, histiocyte-rich B- or T-cell lymphomas or even Hodgkin lymphoma  . AITL-associated macrophages feature M1 or M2 phenotypes  . The AITL milieu appears also to be particularly rich in tryptase-positive mast cells  .
AITL patients have defective T-cell responses, linked to both quantitative and qualitative perturbations of T-cell subsets  and . Whether the significant CD8+ component observed in AITL tissues plays a role in the immunosuppressive background inherent to the disease and/or may exert antitumor properties remains unknown. A depletion in Treg cells and an expansion of M2 macrophages together with an accumulation of Th17 cells (possibly supported by IL-21 and IL-6) reported in AITL tissues could contribute to the pro-inflammatory and immunosuppressive microenvironment in AITL , , and . TGF-β and IL-10 produced by normal TFH cells are known to suppress T-cell responses by inhibiting the proliferation and function of conventional CD4 Th1 cells. TGFβ is also a mediator of FDC differentiation and proliferation. EBV reactivation occurs in the context of a deregulated immune response, which also favors the expansion of both TFH cells and B cells.
2.4. Microenvironment variations
During the course of the disease, a decrease in the microenvironment milieu (i.e. in the polymorphic background and/or FDC expansion) with a parallel increase in neoplastic cells may be seen. This observation has led to the concept of “tumor-cell rich AITL” that can morphologically mimic PTCL, NOS  . Consequently, it is of interest that an experimental model where NOG mice received serial transplantations of AITL cells resulted in the reduction of reactive components such as B cells and CD8+ cells. This suggests that AITL neoplastic cell growth over time becomes independent of interactions with the microenvironment  .
The B-cell blasts can be morphologically and molecularly abnormal, with potential clinical and diagnostic consequences. In some instances they may resemble Hodgkin and Reed–Sternberg cells, usually but not always infected by EBV; these are most often dispersed, resulting in diagnostic difficulties with classical Hodgkin lymphoma. As for Reed–Sternberg cells, AITL-associated atypical B-blasts can show reduced levels of expression of B-cell surface antigens (CD20 and CD79a) and nuclear factors (BOB.1 and OCT2, which are coactivator and the transcription factor of immunoglobulin, respectively) and/or can aberrantly express CD15  and . Additionally, the number of large B-immunoblasts is high (>25%) (B-cell-rich AITL) in a subset of AITL patients, and in some cases, the proliferation of EBV-positive B-cell blasts may be so prominent as to form diffuse confluent sheets. Such cases may be diagnosed as EBV-positive lymphoproliferation or EBV-positive diffuse large B-cell lymphoma. This complication occurs most commonly during the evolution of the disease, but more rarely can be the presenting histologic picture. Less frequently, EBV-negative large B-cell lymphoma or plasma cell proliferations (sometimes monotypic) can also occur , , , and .
A clonal or oligoclonal rearrangement of the IG gene(s) is also found in up to one third of AITL tumor biopsies. B-cell clonality tends to be correlated with higher numbers of B-cell blasts , , and . Intriguingly, most EBV-infected B cells show ongoing mutational activity while carrying hypermutated IG genes with destructive mutations, suggesting that in AITL, alternative pathways operate to allow the survival of these mutating, “forbidden” (Ig-deficient) B cells  . Occasionally, the large B-blasts may harbor genetic aberrations such as BCL6 rearrangements (unpublished observations from FISH experiments).
2.5. Genetic alterations targeting TFH cells
The molecular alterations underlying the neoplastic transformation of TFH cells remain unknown (reviewed in Ref.  ) and whether they have an influence on the interactions between the neoplastic cells and the surrounding cells is not established. Clonal aberrations, most commonly trisomies of chromosomes 3, 5 and 21, gain of X, and loss of 6q, are detected in up to 90% of the cases  .
A role for the c-MAF transcription factor has been suggested, given that transgenic mice develop T-cell lymphomas  , but no aberration at the c-MAF locus has been detected  . Recent works have shown evidence that recurrent point mutations in TET2, IDH2 and DNMT3A, which code for enzymes involved in DNA methylation and epigenetic control of transcription, occur in about 50%, 30–40% and 10% of AITL cases, respectively , , and . TET2 mutations are associated with advanced-stage disease, high IPI scores, and a shorter progression-free survival. These findings and the recent observation that TET2 inactivation could be implicated in the development of TFH clonal expansion in mice may suggest a role for DNA methylation in TFH differentiation and transformation.
A recent study identified CD28-ICOS fusion transcripts in some cases of AITL, a finding of interest given the role of these costimulatory molecules in the interaction between TFH and B cells  . Two PTCL mouse models that could emphasize the importance of the B-cell microenvironment as observed in human AITL have been recently reported. Heterozygous inactivation of Roquin/Rc3h1, a RING type E3 ubiquitin ligase, in mice results in a phenotype recapitulating many clinicopathological features associated with human AITL, including clonal expansion of TFH cells, B and plasma cell expansion and dysimmune manifestations. However, in humans, neither alteration of ROQUIN gene nor deregulation of the expression of miR101, a putative partner of ROQUIN involved in modulation of ICOS expression, were observed  and . In another mouse model, enforced expression of Lin28b, an RNA-binding protein implicated in malignant transformation, leads to an aggressive disseminated CD4+ PTCL of TFH phenotype with a B-cell infiltrate, and accompanied by signs of inflammation such as eosinophilia, release of inflammatory cytokines, and pleural effusion, reminiscent of the symptoms observed in AITL patients  .
2.6. Prognostic and therapeutic implications
The importance of the microenvironment in AITL is also supported by recent findings that a microenvironment-related gene signature may have a prognostic impact in this disease. In a recent study by Iqbal et al.  , AITL with poor prognosis were characterized by a high expression of genes with immunosuppressive functions such as VSIG4, a potent inhibitor of T-cell activation secreted by tolerogenic DCs, as well as receptors or cell-adhesion molecules that mediate proliferative signals, including PDGFRα and PDGFRβ. In contrast, genes associated with B cells (SpiB, BTLA4, SYK), with inhibitory effects on myeloid cell functions (CD200, MIF, SERPINB1), or encoding members of the ribosomal protein synthesis pathway were highly expressed in the good prognostic group. These findings support the role of the microenvironment and provide a rationale for the use of novel therapies targeting the microenvironment. However, in a recent phase 2 study combining immunotherapy (rituximab) and chemotherapy (R-CHOP21), no clear benefit of adding rituximab to conventional chemotherapy was shown  . In this study, the presence of circulating EBV DNA (>100 copy/mg DNA) that correlated with the number of EBV-positive cells in lymph nodes was associated with shorter progression-free survival.
In most studies, pathological characteristics did not show clinical impact on outcome. In particular, in a large study of patients enrolled in clinical trials  , no correlation was found between the cytological variants, the level of expression of CD10 and CXCL13, the number of B-blasts and/or EBV positive cells with survival. In another study, a higher ratio of CD163-positive to CD68-positive cells in AITL significantly correlated with worse overall survival, indicating that macrophage activation toward the M2 phenotype is associated with worse prognosis  .
Recently, elevated IgA levels (>400 mg/dL) were reported as a poor prognostic factor in AITL  . Although this observation requires further investigation, it is noteworthy that TGF-β1 and IL-21 produced by TFH cells, are related to the differentiation of IgA-plasmablasts. It is tempting to speculate that IgA-plasmablasts induced by neoplastic TFH might produce excessive serum IgA  .
3. The germinal center: a major player in T-cell lymphomagenesis
Germinal center (GC)-derived lymphomas include both B-cell and T-cell lymphomas. Remarkably, tumor cells of GC-derived lymphomas proliferate in close association with cellular environment that retains key features of normal GC cellular microenvironment, specifically FDC, macrophages and specific lymphoid subsets  . The prototype of GC-derived B-cell lymphoma is follicular lymphoma, but several other B-cell lymphoma entities appear to originate from cells of the GC, including Burkitt lymphoma, Hodgkin lymphoma and more than one third of diffuse large B-cell lymphomas, emphasizing that a majority of B-cell lymphomas are GC-derived. This is likely related to the fact that GC B cells are exposed to acquired genetic events including mutations of the variable regions of Ig, as well as of several oncogenes that operate in the GC microenvironment  .
A subset of PTCL, NOS with a TFH phenotype and/or AITL-like features, follicular variant of PTCL, NOS and primary cutaneous CD4+ small/medium-sized T-cell lymphoma) ( Fig. 4 )-, it is that the specific minor subset of TFH cells gives rise to the most important group of PTCL, representing more than one third of all PTCL in Europe. Altogether, this might suggest that the GC may provide a critical microenvironment for B and T-cell lymphomagenesis. However, it remains unclear if the GC milieu favors the occurrence of transforming events and/or sustains the survival of transformed T cells.
3.1. Peripheral T-cell lymphoma, not otherwise specified, follicular variant (PTCL-F)
This rare variant of PTCL, NOS includes cases with a truly follicular pattern, mimicking follicular lymphoma  ; and cases with a perifollicular growth pattern mimicking marginal zone lymphoma, or involving expanded mantle zones (progressive transformation of germinal centers-like). The neoplastic cells are CD3+ CD4+ αβ T cells that strongly express TFH markers (PD1+ ICOS+ CXCL13+ BCL6+ CD10+/− CD57−/+)  . A relationship to AITL is suggested since PTCL-F may present biological and clinico-pathological features overlapping with those of AITL and since follow-up biopsies in patients with PTCL-F have documented recurrences manifesting histologically as AITL and vice-versa  and . A chromosomal translocation t(5;9)(q33;q22) involving ITK and SYK tyrosine kinases is found in about 20% of PTCL-F  . ITK-SYK has transforming properties in vitro, and induces a T-cell lymphoproliferative disease in mice through a signal that mimics TCR activation  .
By definition, neoplastic TFH cells in PTCL-F grow in close contact with FDCs and small IgD+ mature B lymphocytes, consistent with the functional properties of TFH cells. While it has been hypothesized that PTCL-F could represent an early step of AITL where the neoplastic TFH develop into GC, the reason(s) why neoplastic TFH in PTCL-F do not spread outside the B-cell follicles through the lymph node and do not associate with significant polymorphic background and hyperplastic veinules, in contrast to AITL, remains unknown. It is noteworthy to mention that TET2 mutations can be found in some PTCL-F, and the molecular signature of PTCL-F exhibits similarities with that of AITL (unpublished data).
3.2. Primary cutaneous CD4+ small/medium-sized T-cell lymphoma
This lymphoproliferation delineated as a provisional lymphoma entity presents as a solitary skin nodule in the head and neck region, and is histologically characterized by a non-epidermotropic dermic infiltrate with atypical small/medium sized cells, accompanied by plasma cells and histiocytes. The atypical cells are clonal CD4+ PD1+ CXCL13+/− BCL6+/− T cells usually negative for CD10  . Most likely as a consequence of the functional properties of TFH cells, an abundant reactive component including B cells, some of which are large and/or EBV-infected, is usually present. A monoclonal TCR gene rearrangement is demonstrated in most cases. Most cases also have features of lesions previously diagnosed as pseudolymphoma, and an indolent clinical course  .
3.3. Peripheral T-cell lymphoma, not otherwise specified expressing TFH markers
Up to one third of cases classified as PTCL, NOS based on their pathological features, have been found to harbor imprints of traces of the TFH signature and/or to express TFH-associated markers. Upon review, a subset of these cases appear to exhibit some AITL-like pathological or clinical features (i.e. B-blasts, some FDC meshwork, EBER scattered cells), and probably represents AITL with a high tumor cell content and partial loss of the AITL-associated microenvironment. This suggests that the spectrum of AITL may be broader than is currently thought , , and . In addition, mutations of TET2 and DNMT3 reported in AITL have also been shown to be more prevalent in this group of PTCL, NOS , , and . It remains to be defined which criteria should be used to define the boundaries of the AITL entity.
4. Microenvironment in other PTCL entities
In PTCL entities other than AITL, the microenvironment is variably represented and qualitatively heterogeneous. A large variety of cell types may be present in addition to the neoplastic component.
Although macrophages are present in low numbers in virtually any tumor in general, a high content in histiocytes is critical in defining rare variants of PTCL entities.
In the lymphohistiocytic variant of ALCL ALK-positive, the neoplastic cells are scattered within a predominant population of reactive histiocytes ( Fig. 1 C). This variant accounts for around 10% of ALK+ ALCL, a disease entity defined by its genetic hallmark, the rearrangement of the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23. This variant occurs exclusively in children and young adults. Compared to the common form of ALK+ ALCL, patients have a more disseminated disease with tendency to a leukemic picture and a worse prognosis with a high risk of failure. These features partly overlap with those of the small cell variant of ALK+ ALCL. In the lymphohistiocytic variant of ALK+ ALCL, the gene expression signature is largely contributed by the histiocytic component  .
The lymphoepithelioid variant of PTCL, NOS (Lennert's lymphoma) is a rare but distinctive subtype, defined as a proliferation of atypical small cytotoxic CD8-positive T-cells admixed with numerous epithelioid histiocytes  . Compared to other PTCL, NOS, the lymphoepithelioid variant tends to be associated with an overall better prognosis  .
Interestingly, PTCL,NOS that are rich in histiocytes, including Lennert's lymphoma, show a molecular signature related to inflammatory response (chemokines, cathepsins, MHC molecules, genes involved in the interferon response pathway) and to the abundant monocyte–macrophage background. The latter appears to be inversely related to a proliferation signature associated with an adverse prognosis  and . Although the clinical and biological relevance of tumor-associated macrophages is largely unknown in most PTCLs, with only one study suggesting their poor prognosis in PTCL, NOS  , molecular studies have highlighted the high expression of genes of the macrophage series in extranodal NK/T-cell lymphoma, nasal-type (ENKTCL) and HSTL  and .
The occurrence of a hemophagocytic syndrome (HPS) – a clinicopathologic syndrome characterized by a systemic activation of benign macrophages with features of hemophagocytosis – is common in T (and NK-) cell-lymphomas. PTCLs associated with HPS are more prevalent in Asian populations often but not always EBV-associated. PTCL associated with HPS include aggressive NK-cell lymphoma/leukemia, ENKTCL, HSTL, subcutaneous panniculitis-like T-cell lymphoma, cutaneous γδ T-cell lymphoma, and more rarely, PTCL, NOS or EATL  . Clinically, patients present with prominent symptoms of HPS, i.e. severe B symptoms, pancytopenia, splenomegaly and/or hepatomegaly, but only few or no lymphadenopathies. Biological features of macrophage activation include increased ferritinemia and hypertriglyceridemia  . HPS is generally considered as a T-cell-mediated syndrome with hypercytokinemia, but the roles that infectious agents, macrophages, and T cells play in its pathogenesis is not fully understood. An attractive model implicating EBV infection in T-cell activation and transformation as well as in macrophage activation has been proposed that involves multiple cytokines and chemokines ( Fig. 5 )  . EBV LMP-1 is known to be the oncogenic protein responsible for the activation of nuclear factor-kappaB (NF-kB) and for enhanced cytokine secretion  . The activation of NF-kB confers resistance to TNF-alpha-induced apoptosis in EBV-infected T cells by downregulating TNFR-1. Consistent with in vitro observations, EBV-associated T- or NK-cell lymphoma show constitutive activation of NF-kappaB, supporting hypercytokinemia, as well as drug resistance and poor prognosis. Interestingly, Herpes virus Papio, an EBV-like virus, induces fatal lymphoproliferative disorders with HPS in rabbits  . A possible relationship between secondary HPS and familal hemophagocytic lymphohistiocytosis is not known. However, mutations of the gene, described in the familial form of hemophagocytic lymphohistiocytosis, have been occasionally reported in patients with lymphoma  .
Microvessels represent an important component of the tumor microenvironment in PTCLs. In some PTCL entities, peculiar growth patterns related to vessels are observed that may be used as diagnostic features.
4.3. Vascular patterns in PTCLs
- - Elective intrasinusal distribution within sinuses/sinusoids of the bone marrow, spleen and liver is a characteristic feature of HSTL that contrasts with the absence of leukemic dissemination at presentation. This elective distribution accounts for the peculiar clinical presentation of HSTL, which is characterized by hepatosplenomegaly and cytopenias without lymphadenopathy. High levels of expression of the sphingosine-1-phosphatase receptor 5 (S1PR5) in HSTL might provide the molecular basis for this peculiar distribution  . Indeed S1PR5 encodes a member of the family of S1P receptors, which are involved in T- and B-cell exit from lymphoid organs, and which are preferentially expressed by mature CD56dim human NK cells. Since S1PR5-deficient mice have defective homing of NK cells to the blood and spleen, it can be hypothesized that high levels of S1PR5 in HSTL could prevent tumor cells from exiting sinusoids. Whether cell–cell interactions involving the cell adhesion molecule LFA1 (CD11a), expressed by HSTL cells; and VCAM1, expressed by splenic sinusoidal cells, also play a role in the clinicopathologic picture of the disease remains to be determined.
- - Systemic ALCL (ALK+ and ALK-negative) has a propensity for invading the lymph node sinuses, mimicking a metastatic pattern of growth as well as exhibiting a perivascular distribution of lymphoma cells. These features are particularly useful for the identification of the small cell and lymphohistiocytic variants of ALK-positive ALCL  . It has been suggested that these features reflect ALK-mediated signaling pathways, in particular changes in cytoskeleton organization following activation of RHO family GTPases by VAV guanine nucleotide exchange factors, which in turn, are directly or indirectly phosphorylated/activated by NPM-ALK.
- - ENKTL, nasal-type, a distinct entity associated with EBV and that most often originates from NK cells, is characterized by an angiocentric and angioinvasive pattern of growth, which causes common vascular damage and tissue necrosis. Angiocentricity might be explained by the high expression of genes such as VCAM1, CXCL9, and CXCL10, which encode proteins involved in the interaction with endothelium  . Gene expression profiling of ENKTCL has revealed overexpression of genes involved in angiogenic pathways  . Tissue damage has been linked to high levels of IP-10 and Mig by endothelial cells, macrophages, and lymphocytes, and abnormally elevated circulating levels of IP-10  .
Among non-Hodgkin lymphomas, PTCLs demonstrate the highest microvessel density  . Increased microvessel density has also been shown in cuteanous biopsies involved by MF in comparison with inflammatory skin conditions  . VEGF overexpression in PTCL, NOS has been associated with a poor outcome  . VEGF may result in local neovascular transformation (angiogenesis) and recruitment of circulating progenitors derived from the bone marrow (vasculogenesis)  . However, in contrast to AITL, it is unclear which cell type(s) release VEGF and whether VEGF receptors are present and functional on the lymphoma cells in PTCL, NOS. In models of NPM-ALK-driven oncogenesis, STAT3 induces VEGF expression by the lymphoma cells. MicroRNA-135b is another mediator of NPM-ALK-mediated angiogenesis  . Elevated serum VEGF levels in patients with non-Hodgkin lymphoma have been reported to be associated with a poor outcome  . Attempts to improve the outcome of PTCL patients by adding bevacizumab (a humanized monoclonal antibody against VEGF) have, however, proven ineffective  .
Blood and tissue eosinophilia may be seen in various PTCLs as a result of non-clonal expansion of normal eosinophils mediated by eosinophilopoietic growth factors, such as interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) and the highly specific eosinophilopoietic cytokine IL-5 (for review see Roufosse et al.  ). These cytokines are normally produced by activated T cells (IL-3 and GM-CSF by Th1 and Th2, and IL-5 by Th2-polarized helper T cells). Other factors promoting eosinophil chemotaxis include RANTES (regulated on activation normal T cell expressed and secreted)/CCL5) and eotaxins 1-3 (CCL11, CCL24, CCL26). RANTES also exerts chemoattractant activity for T lymphocytes, monocytes, and basophils, and is produced by a variety of cell types, including T cells, fibroblasts, and epithelial cells. Eotaxins signal through CCR3 receptor, which is expressed at high levels on eosinophils and Th2 cells. Cellular sources of eotaxin include fibroblasts, endothelial cells, eosinophils, and lymphocytes.
PTCLs most commonly associated with eosinophilia include primary cutaneous T-cell lymphomas (CTCL), AITL and adult T-cell leukemia/lymphoma (ATLL). Hypereosinophilia is less frequent in PTCL, NOS, EATL (51), and ENKTCL. 15–20% of patients with MF and up to 75% of those with Sezary Syndrome (SS) develop blood eosinophilia and show numerous eosinophils within cutaneous lymphoma infiltrates. Eosinophilia in MF and SS, is related to the Th2 nature of the lymphoma cells, which produce IL-4, IL-5, and IL-13. The recruitment of eosinophils to the skin is mediated by chemoattractants produced by the lymphoma cells but also possibly by other cell types. Indeed, IL-4-producing lymphoma cells induce increased expression of eotaxin-3/CCL26 by keratinocytes, endothelial cells, and fibroblasts  and . In cutaneous ALCL as well lymphomatoid papulosis (type A), a reactive inflammatory infiltrate may be found within the tumor, and eosinophils may be detected in a substantial proportion of patients  , occasionally representing the predominant cell type. CD30+ tumor cells isolated from skin biopsies with cutaneous ALCL have been shown to co-express CCR3 and IL-4, and eotaxin in conjunction with surrounding cells, indicating that they contribute to eosinophilic infiltrates  .
Roughly one fifth of patients with ATLL also have blood eosinophilia secondary to the secretion of IL5 and GM-CSF s by ATLL cells. The HTLV-1-encoded transactivator, tax, may contribute to cytokine production by HTLV-transformed cells  . In one study, tumor-infiltrating eosinophils in PTCL, NOS biopsies were correlated with the presence of IL-5 in lymphoma cells, and of TARC in scattered reactive cells with dendritic cell morphology  . In most instances, blood eosinophilia has been associated with an unfavorable prognosis  and .
A lymphocytic variant hypereosinophilic syndrome (L-HES) has been recently reported. It is defined as persistent hypereosinophilia associated with eosinophilic tissue infiltrates (predominantly but not exclusively in the skin), in the setting of a clonal expansion of mature “Th2-like” T-cells with abnormal expression of T-cell antigens (i.e. CD3−/dimCD4+ (the most commonly reported subset), CD3+CD4−CD8−, and CD3+CD4+CD7−) and producing eosinophilopoietic factor(s) (for review, see Roufosse et al.  ). The CD3−CD4+ T-cells also produce IL-4 and IL-13, explaining the marked elevation of serum TARC levels observed in untreated patients. The underlying defect leading to expansion of these clonal “Th2-like” lymphocytes remains unknown. A subset of HES patients with clonal IL-5-producing T-cells will eventually develop full-blown PTCL.
The functional role of eosinophils within the tumor microenvironment remains poorly characterized. Eosinophils also produce IL-5 and since they also express the cognate receptor, autocrine activation is possible. Clinical and experimental investigations have shown that eosinophils can function as antigen-presenting cells and can promote the proliferation of effector T cells. In addition, eosinophils are able to produce an array of cytokines (IL-2, IL-4, IL-6, IL-10, and IL-12) capable of promoting T-cell proliferation, activation, and influencing Th1-Th2 polarization, thereby regulating tumor cell growth and expansion  .
4.6. Epitheliotropic features
Epitheliotropism is a defining feature of some PTCL entities. In MF and SS, the cutaneous lymphocyte-associated antigen (CLA), commonly expressed by lymphocytes when recruited in the skin (in inflammatory and neoplastic conditions) might explain the specific homing of neoplastic cells into the skin and the epidermis. Loss of CD26 by Sézary cells – a membrane-associated peptidase able to cleave SDF-1, the CXCR4 receptor expressed by Sézary cells, might also favor skin homing through SDF1-CXCR4 interaction  .
EATL, a rare complication of celiac disease, is a distinct entity that develops from the intraepithelial T-lymphocytes (IEL) of the intestine. In genetically predisposed subjects (HLA-DQ/DQ8), the gluten peptides are able to activate CD4+ cells, which secrete IFN and activate different pathways. These events lead to mucosae changes such as villous atrophia, expansion of IELs and crypt hyperplasia, which are typical features of celiac disease. This process emphasizes an important crosstalk between cytotoxic IELs that accumulate in the intestinal epithelium, the dendritic cells, macrophages and epithelial cells. The alpha(E)beta(7) integrin (CD103) also facilitates retention of lymphocytes in the intestinal epithelial layer through interactions with its epithelial cell ligand, E-cadherin. Although the molecular oncogenic events in EATL are not fully deciphered, increased IL-15 levels in mucosa of patients with celiac disease and EATL could also contribute to apoptosis deregulation and transformation of IELs (reviewed in Ref.  ).
Despite the wide variation across entities, an abundant microenvironment component appears to be a characteristic feature of PTCL. As in classical Hodgkin lymphoma, the reactive cellular component, including eosinophils, macrophages, vessels, mast cells, reactive T lymphoctes, and B cells, can dominate and even obscure the neoplastic cell population, as shown in AITL. This supports the importance of an appropriate niche for the growth of neoplastic T or NK cells.
Although the functional interactions between the various cellular components have only been partly deciphered, several lines of evidence suggest that non-neoplastic elements concur with the malignant phenotype and the clinical features. Consequently, the development of novel therapeutic approaches targeting the microenvironment represent attractive adjuncts or alternatives to conventional chemotherapy regimens to improve the poor outcome of most PTCL patients.
Conflict of interest
The authors have no financial disclosure or conflict of interest.
The authors are very thankful to Maria Pamela Dobay for her critical reading and editing of the manuscript. Philippe Gaulard and Laurence de Leval are supported by the Institut National du Cancer (INCa) (FOHLY project), the Plan Cancer of the Belgian government, the Recherche Suisse contre le Cancer, the Medic Foundation and by the Fondation pour la Recherche Médicale (DEQ 2010/0318253).
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a Department of Pathology, AP-HP, Groupe hospitalier Henri Mondor – Albert Chenevier, Créteil, France
b Université Paris-Est, Faculté de Médecine, Créteil, France
c INSERM, U955, Institut Mondor de Recherche Biomédicale, Créteil, France
d Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
© 2013 Published by Elsevier B.V.