Summary
Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. ...Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.
CD4+ T-cell subsets are found in the tumour microenvironment (TME) of low-grade B-cell non-Hodgkin's lymphomas such as marginal zone lymphoma (MZL) or follicular lymphoma (FL). Both numbers and ...architecture of activating follicular helper T-cells (Tfh) and suppressive Treg in the TME of FL are associated with clinical outcomes. There has been almost no previous work on CD4+ T-cells in MZL. It is now recognised that circulating CD4+CXCR5+ T-cells are the memory compartment of Tfh cells. We determined differences in number of circulating Tfh (cTfh) cells and cTfh subsets between normal subjects and patients with FL or MZL. Lymphoma patients showed increased numbers of cTfh1 and reduced cTfh17 cells due to decreased expression of the subset-defining marker CCR6 in patients. PD1, a surface marker associated with Tfh cells, showed increased expression on cTfh subsets in patients. Focusing on MZL we determined expression of 96 T-cell associated genes by microfluidic qRT-PCR. Analysis of differentially expressed genes showed significant differences between normal subjects and patients both for bulk cTfh (CCL4) and the cTfh1 subset (JAK3). While our findings require confirmation in larger studies we suggest that analysis of number and gene expression of circulating T-cells might be a source of clinically useful information as is the case for T-cells within lymphoma lymph nodes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of the microenvironment in high-grade lymphoma is not well defined. In this report, we employ immunohistochemistry to characterise programmed death-1 (PD-1/CD279) and FoxP3 expression in 70 ...cases of diffuse large B-cell lymphoma (DLBCL). PD-1 is a surface marker characteristic of follicular helper T-cells whilst FoxP3 is characteristic of Tregs. We demonstrate variable infiltration with CD4
+
T-cells (<10 to >50 % of all lymph node cells) and PD-1
hi
cells (0.1 to 1.5 % of all cells). CD4
+
T-cells can be distributed in clusters or more diffusely and PD-1
hi
cells, but not FoxP3
+
cells, are found in rosettes around lymphoma cells. Cases with high CD4
+
T-cell numbers tended to have higher numbers of both PD-1
hi
and FoxP3
+
cells. Cases with total CD4
+
T-cell, PD-1
hi
and FoxP3
+
numbers above the median associate with better clinical outcome. Overall, we demonstrate that infiltration by CD4
+
T-cells, including both FoxP3
+
and PD-1
hi
subsets, correlates with prognosis in DLBCL. In distinction to previous reported series, patients (91 %) were treated with rituximab-containing regimens, suggesting that the effects of CD4+ T-cell infiltration are maintained in the rituximab era. This work suggests that determinants of total CD4
+
T-cell infiltration, either molecular characteristics of the lymphoma or the patients’ immune system, and not individual T-cell subsets, correlate with clinical outcome.
Patients with peripheral T-cell lymphomas generally have poor clinical outcomes with conventional chemotherapy. Recent advances have demonstrated that a large subgroup of PTCL are derived from ...follicular helper (Tfh) T-cells. These cases show a characteristic pattern of gene expression, which includes high-level protein expression of interleukin-2-inducible kinase (ITK). ITK is a member of the TEC family of kinases and normally has essential functions in regulating T-cell receptor signalling and T-cell differentiation. Here we report a side-by-side comparison of four ITK inhibitors. We investigate effects on apoptosis, phosphorylation of signaling molecules, calcium flux and migration. In line with a specific mechanism of action ONO7790500 and BMS509744 did not inhibit MEK1/2 or AKT phosphorylation although other ITK inhibitors, ibrutinib and PF-06465469, did have this effect. Specific ITKi had modest effects on apoptosis alone but there was definite synergy with doxorubicin, pictilisib (PI3Ki) and idelalisib (PI3Kδi). ITKi repressed migration of Jurkat cells caused by CXCL12 and the CXCR4 antagonist, plerixafor enhanced this effect. Overall ITKi may have several mechanisms of action that will be therapeutically useful in PTCL including reduction in survival and perturbation of trafficking.
Summary
Follicular helper T‐cells (Tfh cells) are a subset of CD4+ T‐cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and ...show high expression of surface markers CXCR5, ICOS, PDCD1 (PD‐1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T‐cell non‐Hodgkin lymphoma: angioimmunoblastic T‐cell lymphoma (AITL) and ~20% of peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL‐NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre‐clinical development.
Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain ...bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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