tissue sections, a close contact is observed between neoplastic AITL cells, FDCs and B cells, the three important key players in the disease (Figure 2.2). Large B immunoblasts, often infected by EBV, interact with neoplastic Tfh cells, as exemplified by the rosettes of neoplastic Tfh cells 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) and cytokines/chemokines secretion. CXCL13 secreted by neoplastic Tfh cells is likely a major mediator that can promote B‐cell expansion and plasmacytic differentiation. In addition, CXCL13‐producing FDCs could also interact with neoplastic Tfh cells which express CXCR5, resulting in localization of these cells to the germinal center [63]. Lymphotoxin beta, also expressed in AITL tumor cells [64], might be involved in inducing FDC proliferation. Interleukin (IL) 6 produced by Tfh cells and myeloid cells can promote plasma cell proliferation [65]. IL21, the major cytokine secreted by Tfh cells, exhibits an autocrine effect on the IL21‐positive Tfh, and also exerts positive effects on B cells. The role of VEGF and its receptor, both expressed by neoplastic and endothelial cells in AITL, has been proposed in promoting vascularization observed in the disease. A number of chemokines, like CCL17/TARC, or cytokines such as IL4, IL5, and IL13 demonstrated in CD3+ T cells isolated from AITL lymph nodes, are potential mediators of eosinophilic infiltrate in tissue biopsies and/or eosinophilia [66]. AITL also comprises a variable number of macrophages, with various phenotypes and functions [67].
Variation in microenvironment may have prognostic relevance, reinforcing its role in lymphomagenesis. Tissue infiltration of CD163‐positive macrophages has been shown to associate with worse prognosis in patients with AITL, suggesting their importance in AITL [67]. A depletion of Treg cells and an expansion of CD163 macrophages together with an accumulation of Th17 cells reported in AITL tissues could contribute to the proinflammatory and immunosuppressive microenvironment in AITL [68]. Gene expression studies identified molecular signatures associated with outcome [69, 70]. For example, The B‐cell‐associated signatures predicted favorable outcome, whereas monocytic, cytotoxic (associated with CD8 + T cells) and p53‐induced target gene signatures were associated with poor outcome [70].
Genetic Alterations in the Angioimmunoblastic T‐cell Lymphoma Microenvironment
Recent genetic studies at the single‐cell level have shed a new light onto the bystander cells in AITL. Since founding mutations in epigenetic modifiers have been found to occur in a hematopoietic CD34+ precursor or stem cell before lineage commitment [17, 31], TET2 and DNMT3A mutations can be detected not only in neoplastic T cells, but also in B cells isolated from AITL biopsies [71, 72]. Variant allele frequencies of TET2 and DNMT3A are usually higher than those of T‐cell restricted RHOA or IDH2 variants [14], indicating that epigenetic deregulation more widely affects the different cellular components of the tumors. Moreover, the B blasts, in addition to those infected with EBV, can show a restricted repertoire of hypermutated IG genes with destructive mutations [73], and may harbor additional somatic mutations, notably in NOTCH1 [72]. It is likely that this could hold true for reactive CD8+ T cells often abundant in AITL tissues and for mononucleate cells of myeloid lineage. In this respect, it is noteworthy that co‐occurrence of myeloproliferative disorders like acute myeloid or chronic myelomonocytic leukemia and AITL have been reported in some patients [74–76]. Both diseases may derive from a common ancestral progenitor harboring TET2 and/or DNMT3A mutations and/or high‐risk clonal hematopoiesis, with subsequently acquisition of distinct mutations initiating the divergent development of AITL and myeloid disease [75]. Altogether, these findings indicate that several components of the microenvironment can be genetically altered in AITL, and it is tempting to speculate that genetically altered bystander cells could also contribute to AITL pathogenesis (Figure 2.2). The role of EBV in this disease remains debated. It infects a variable number of large B blasts in around 80% of cases, with a latency type 2, but the question whether EBV has any oncogenic role or is present as a passenger, reflecting the immune defect observed in AITL, remains open. Indeed, transforming growth factor beta and IL10 produced by Tfh cells are known to suppress T‐cell responses by inhibiting the proliferation and function of conventional CD4 Th1 cells, and may play a role in the expansion of EBV‐positive B cells.
Specific Microenvironment Components Present in Other Primary Cutaneous T‐cell Lymphoma Entities
A microenvironment component is present in all PTCL entities. Here, we review the data relative to distinct cellular components.
Macrophages
A high content in histiocytes is present in some PTCL entities. For example in the lymphohistiocytic variant of ALCL ALK‐positive, which occurs exclusively in children and young adults, the gene expression signature is largely contributed by the histiocytic component and, in comparison to the classical disease the patients have a more disseminated disease with tendency to a leukemic picture and a worse prognosis with a high risk of failure [77]. Conversely, the lymphoepithelioid variant of PTCL, NOS tends to be associated with an overall better prognosis than other PTCL‐NOS [78, 79]. In PTCL, NOS rich in histiocytes, the molecular signature related to inflammatory response (chemokines, cathepsins, major histocompatibility complex (MHC) molecules, genes involved in the interferon response pathway) and to the monocyte–macrophage background appears to be inversely related to a proliferation signature and associated with an adverse prognosis [80, 81].
Angiogenesis
Among non‐Hodgkin lymphomas, PTCLs demonstrate the highest microvessel density [82]. Increased microvessel density has also been shown in cutaneous biopsies involved by mycosis fungoides in comparison with inflammatory skin conditions [83]. VEGF overexpression in PTCL, NOS has been associated with a poor outcome [84]. VEGF may result in local neovascular transformation (angiogenesis) and recruitment of circulating progenitors derived from the bone marrow (vasculogenesis) [85]. 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 [86]. Elevated serum VEGF levels in patients with non‐Hodgkin lymphoma have been reported to be associated with a poor outcome [87]. Attempts to improve the outcome of patients with PTCL by adding bevacizumab have, however, proven ineffective [88].
Figure 2.2 Neoplastic T follicular helper cells and their microenvironment in angioimmunoblastic T‐cell lymphoma. B, B cell; EBV, Epstein–Barr virus; FDC, follicular dendritic cell; IL, interleukin; LT‐β, lymphotoxin‐beta; MAC, macrophage; PC, plasma cell; TFH, T follicular helper cells; TGF, transforming growth factor; Th1, T lymphocyte 1; Treg, T regulatory cells (gray arrows: epigenetic mutations, which may occur early and may be detected in neoplastic cells and other reactive cells including B cells; asterisk: additional mutations or somatic hypermutations; red arrows: T‐cell‐specific mutations like RHOA G17V or others.
Source: Adapted from de Leval and Gaulard [63].
Eosinophils
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 IL3, granulocyte‐macrophage colony stimulating factor and IL5 normally produced by activated T cells (for review see Roufosse F et al. [89]). 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,