the immune control is one of the hallmarks of cancer. Two main mechanisms of immune escape may be employed. On the one hand, neoplastic cells can overexpress surface ligands such as PDL1, PDL2, which, after receptor engagement, result in anergy of tumor infiltrating lymphocytes. On the other hand, T and NK neoplastic cells may avoid immune recognition through the loss of class I CMH and or beta2 microglobulin alterations and CD58 anomalies. CD58 is a member of immunoglobulins superfamily which acts as a ligand for CD2 that allows activation of T and NK cells. Those alterations are found in several lymphomas, especially in diffuse large B‐cell lymphomas [58]. It is noteworthy that alterations in CMH and beta 2 microglobulin or CD58, impairing the recognition by T or NK cells have been described in ATLL [46] and PTCL‐NOS [53].
The efficacy of immunotherapy such anti‐PD1 or anti‐CTLA4 antibodies in several cancers also reinforces the importance of immune escape of neoplastic cells. However, targeting the immune system in PTCL is far more complex, as the neoplastic targets are T cells themselves, in which the TCR, co‐stimulation system and cytokines receptors may be functional. As mentioned above, structural variants in the 3′ UTR part of PDL1 have been reported in ATLL [9], ENKTL or other EBV‐related T‐ or NK‐cell lymphomas [10]. The 3′ UTR is a region allowing posttranscriptional regulation of mRNA level through action of microRNA or regulating proteins. These structural variants result in PDL1 overexpression, contributing to immune escape. It is noteworthy that relapsed/refractory ENKTL show a high response rate to anti‐PD1 therapy [59].
In CTCL, a gene fusion between CD28 and CTLA4 results in a chimeric receptor with the extracellular domain of CTLA4 and the intracellular domain of CD28 [60]. This CTLA4–CD28 fusion converts the negative inhibitory effect normally exerted by CTLA4 ligands expressed by reactive cells surrounding neoplastic T cells, into an activating signal driven by the intracellular CD28‐derived segment of the chimeric receptor. In this setting, deregulated signaling resulting from the structural change of the receptor, is not autonomous and exemplifies the cooperation between microenvironment and intrinsic changes in the neoplastic cells.
Role of the Microenvironment in Peripheral T‐cell Lymphoma
In PTCLs, the microenvironment, reactive cells and stroma, is quantitatively and qualitatively variable. However, its characterization remains largely unexplored and the functional interactions between the microenvironment and neoplastic components poorly understood.
The Model of Angio‐immunoblastic T‐cell Lymphoma and T Follicular Helper‐derived Peripheral T‐cell Lymphoma
AITL exemplifies a disease with a major microenvironment component. Its designation itself reflects the typically prominent vascularization of high endothelial venules and the presence of reactive immunoblasts. In fact, the neoplastic cells are often outnumbered by a polymorphous infiltrate comprising not only large B‐cell blasts, but also plasma cells, follicular dendritic cells (FDCs), reactive CD4 and CD8 T lymphocytes, eosinophils, macrophages, and mast cells. At the molecular level, up to 90% of the AITL gene expression signature can be attributed to the microenvironment, with overexpression of B‐cell (including immunoglobulins) and FDC‐related genes, chemokines and chemokine receptors (CCL19, CCL20, CCL22, CCL24, IL4) and genes related to extracellular matrix and vascular biology (such as vascular endothelial growth factor [VEGF], thrombomodulin, angiopoietin 2) [61].
A complex network of interactions between the lymphoma cells and other cell components likely takes place, and a dependency on the microenvironment is also supported by the fact that a self‐sustaining lymphoma cell line could not be established so far.
Crosstalk Between Neoplastic T Follicular Helper Cells and Their Microenvironment in Angioimmunoblastic T‐cell Lymphoma
The cellular derivation of AITL from Tfh cells provides a rational model to explain the formation of the characteristic AITL microenvironment. Tfh cells represent a distinct functional subset of effector T‐helper (Th) cells, which normally reside in germinal centers where critical interactions with germinal center B cells promote B‐cell survival, immunoglobulin class‐switch recombination and somatic hypermutation, ultimately yielding high‐affinity plasma cells and memory B cells [62].
On 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
