Dataset Information

Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients.

ABSTRACT:

Background

In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4⁺ T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties.

Methods

Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n?=?25) and healthy volunteers (n?=?25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-?, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT² Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test.

Results

In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4⁺ and TH17 IL-17A⁺ cells, and a higher percentage of IFN-?/IL-10 and IL-4/IL-10 double-releasing CD4⁺ T cells. In addition, we also observed the up-regulation of innate immunity genes and the down-regulation of adaptive immunity ones.

Conclusions

Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.

SUBMITTER: De Matteis S

PROVIDER: S-EPMC6011245 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients.

De Matteis Serena S Molinari Chiara C Abbati Giulia G Rossi Tania T Napolitano Roberta R Ghetti Martina M Di Rorà Andrea Ghelli Luserna AGL Musuraca Gerardo G Lucchesi Alessandro A Rigolin Gian Matteo GM Cuneo Antonio A Calistri Daniele D Fattori Pier Paolo PP Bonafè Massimiliano M Martinelli Giovanni G

Journal of translational medicine 20180620 1

<h4>Background</h4>In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4<sup>+</sup> T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties.<h4>Methods</h4>Peripheral blood mononuclear cells were isolated from newly dia ...[more]

PMID: 29925389

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Project description:BackgroundImpaired neutrophil activity is an important issue in chronic lymphocytic leukemia (CLL), as it contributes to a dysfunctional immune response leading to life-threatening infections in patients. Some features typical of CLL neutrophils, e.g., the B-cell-supportive secretion profile, have already been described. However, most of these studies were performed on cells isolated from peripheral blood. It is still unclear which molecular factors and cell types are involved in shaping neutrophil function and phenotype in the CLL microenvironment. Since regulatory T cells (Treg) play an important role in CLL progression and influence the activity of neutrophils, we investigated the crosstalk between Treg and neutrophils in the spleen using a murine model of CLL.MethodsIn this work, we used an Eµ-TCL1 mouse model of human CLL. For our in vivo and ex vivo experiments, we inoculated wild-type mice with TCL1 leukemic cells isolated from Eµ-TCL1 transgenic mice and then monitored disease progression by detecting leukemic cells in peripheral blood. We analyzed both the phenotype and activity of neutrophils isolated from the spleens of TCL1 leukemia-bearing mice. To investigate the interrelation between Treg and neutrophils in the leukemia microenvironment, we performed experiments using TCL1-injected DEREG mice with Treg depletion or RAG2KO mice with adoptively transferred TCL1 cells alone or together with Treg.ResultsThe obtained results underline the plasticity of the neutrophil phenotype, observed under the influence of leukemic cells alone and depending on the presence of Treg. In particular, Treg affect the expression of CD62L and IL-4 receptor in neutrophils, both of which are crucial for the function of these cells. Additionally, we show that Treg depletion and IL-10 neutralization induce changes in the leukemia microenvironment, partially restoring the "healthy" phenotype of neutrophils.ConclusionsAltogether, the results indicate that the crosstalk between Treg and neutrophils in CLL may play an important role in CLL progression by interfering with the immune response.

Project description:Previous studies have shown increased familial risk for chronic lymphocytic leukemia. In the most comprehensive study to date, we evaluated risk of chronic lymphocytic leukemia and lymphoproliferative disorders among first-degree relatives of chronic lymphocytic leukemia cases compared to first-degree relatives of controls.Population-based registry data from Sweden were used to evaluate outcomes in 26,947 first-degree relatives of 9,717 chronic lymphocytic leukemia patients (diagnosed 1958-2004) compared with 107,223 first-degree relatives of 38,159 matched controls. Using a marginal survival model, we calculated relative risks (RR) and 95% confidence intervals as measures of familial aggregation.Compared to relatives of controls, relatives of chronic lymphocytic leukemia patients had an increased risk for chronic lymphocytic leukemia (RR=8.5, 6.1-11.7) and other non-Hodgkin's lymphomas (NHLs) (RR=1.9, 1.5-2.3). Evaluating NHL subtypes, we found a striking excess of indolent B-cell NHL, specifically lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and hairy cell leukemia. No excesses of aggressive B-cell or T-cell lymphomas were found. There was no statistical excess of Hodgkin's lymphoma, multiple myeloma, or the precursor condition, monoclonal gammopathy of undetermined significance, among chronic lymphocytic leukemia relatives.These familial aggregations are striking and provide novel clues to research designed to uncover early pathogenetic mechanisms in chronic lymphocytic leukemia including studies to identify germ line susceptibility genes. However, clinicians should counsel their chronic lymphocytic leukemia patients emphasizing that because the baseline population risks are low, the absolute risk for a first-degree relative to develop chronic lymphocytic leukemia or another indolent lymphoma is low. At this time, an increased medical surveillance of first-degree relatives of chronic lymphocytic leukemia patients has no role outside research studies.

Project description:Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Dataset Information

Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients.

Background

Methods

Results

Conclusions

Publications

Immunosuppressive Treg cells acquire the phenotype of effector-T cells in chronic lymphocytic leukemia patients.

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