The Peripheral T-Cell Lymphomas. Группа авторов
in T‐cell activation and proliferation. In addition, the functional differentiation of CD4+ cells relies on different JAK–STAT family members (for example, STAT1/STAT4 seems to be involved in Th1 differentiation, STAT6 in Th2, STAT3 in Th17 and STAT5 in Treg polarization) [48]. Activation of the JAK–STAT pathway is common to several PTCLs, and is particularly frequent in cytotoxic lymphomas. In ALK‐positive ALCLs ALK fusion proteins lead to activation of the JAK–STAT3 signaling [49]. Alternative mechanisms of JAK–STAT3 activation are observed in the majority of ALK‐negative ALCLs, including mutations in JAK1 and/or STAT3 in up to 20% ALK‐negative ALCL and fusions involving ROS1, TYK2, or FRK. In these lymphomas, co‐occurring mutations in two genes of the JAK/STAT pathway for example in STAT3 and JAK1 could act synergistically to amplify JAK/STAT signaling and sustain cell transformation [28, 50]. STAT3 mutations are detected in one third of large granular lymphocyte leukemia [51]; JAK3, STAT3, and STAT5B mutations in a proportion of ENKTL, nasal type [26, 52]; JAK3 and above all STAT5B mutations in up to 60% of MEITL [23], whereas STAT5B, or more rarely STAT3 are mutated in 30 and 10% of HSTL, respectively [24]. These mutations are associated with increased JAK–STAT signaling, as suggested by the increased nuclear expression of pSTAT3 or pSTAT5 in mutated cases. In addition, inactivating mutations in negative regulators (SOCS1, SOCS3, PTPN1, and others) of the pathway may also contribute to increasing JAK–STAT signaling [28].
Cell‐cycle Control
TP53, the gene that encodes for p53, the guardian of the genome, is probably the most studied tumor suppressor gene. P53 regulates multiple cellular functions, such as DNA repair, cell‐cycle arrest, apoptosis, senescence, and metabolism. TP53 mutations or deletions are found in around 50% of cancers, and commonly correlate with chemoresistance and poor prognosis. Inactivating TP53 mutations are reported with a variable frequency, being uncommon in Tfh‐derived PTCL, and more frequent in PTCL‐NOS. In particular, a PTCL‐NOS subset characterized by genomic instability and a poorer prognosis, partially overlapping with the GATA3–3‐positive molecular subgroup [6] is enriched in TP53 anomalies [6, 53]. In ATLL, TP53 mutations are found in less than 20% of the patients, where they associate with chemoresistance and short survival [46]. They are also common in extranodal PTCL, such as ENKTL [25] and enteropathy‐associated T‐cell lymphoma (EATL) [54].
In addition to TP53 inactivation, CDKN2A deletions have also been reported in several PTCLs. CDKN2A, located on chromosome 9, encodes for two transcripts, p16INK4a and p14ARF. p16INK4a is involved in cell‐cycle regulation, via inhibition of cdk4 and cdk6, resulting in activation of retinoblastoma proteins, while p14arf controls MDM2 activity via sequestration. MDM2 is an E3 ubiquitin ligase that recognizes the N‐terminal transactivation domain of the p53 tumor suppressor, resulting in its degradation. Thus, CDKN2A deletion can result in increased MDM2 function and excessive p53 degradation. CDKN2A deletions are frequent in CTCL, especially in aggressive forms, as they are observed in more than 50% of patients in transformed mycosis fungoides or Sézary syndrome, while they are rare in CD30+ cutaneous ALCL [55]. In ATLL, CDKN2A deletions are reported in 50% of patients with the acute form, but in only 20% of patients with chronic clinical variants of the disease [56]. Deletion of CDKN2A, found in up to 50% of patients with PTCL‐NOS with enrichment in GATA3/Th2 signature, is reported to correlate with shorter survival and poor prognosis [6, 53].
TP63 is rearranged in a small proportion (< 10%) of ALCL, where it correlates with intense P63 expression [2]. Although TP63 is a TP53 homolog, its role as a tumor suppressor gene is unclear. However, cases with TP63 rearrangement correlate with an aggressive clinical behavior [2, 57].
Immune Surveillance
The immune system perpetually eradicates the formation and progression of incipient neoplasia, and evading 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