The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

Yousefi, Mehdi; Movassaghpour, Aliakbar; Shamsasenjan, Karim; Ghalamfarsa, Ghasem; Sadreddini, Sanam; Jadidi‐Niaragh, Farhad; Hojjat‐Farsangi, Mohammad

doi:10.2217/fon.14.298

Cited by 27 publications

(19 citation statements)

References 146 publications

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“…With regard to the down-regulation of important genes involved in T cell development and differentiation, e.g. CXCR3, IL - 23A and RORC , we hypothesize a mechanism of negative regulation related to a sub-subset of TH17 known as TH17-23 which generates the effector cells involved in anti-tumor immunity [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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BackgroundIn 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.MethodsPeripheral 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-γ, 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.ResultsIn 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-γ/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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1545-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…It is clear that the cellular and cytokine microenvironment surrounding leukemic B cells greatly influences the growth and survival of the clone, providing pro- and antitumor signals [ 3 ]. T cell dysregulation is a common feature of CLL, characterized by impaired immune synapse formation and altered T-subset balance [ 6 – 8 , 13 ]. The role of T cell subset balance in host antitumor immune responses is complex and incompletely understood, with specific subsets having variable and at times opposite effects in the setting of different tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes

et al. 2015

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Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4+ T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4+ T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL-17F triggers NFκB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals.Electronic supplementary materialThe online version of this article (doi:10.1007/s12026-015-8722-5) contains supplementary material, which is available to authorized users.

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“…are the main types of the TILs in the tumour microenvironment during chronic inflammation 12,13 ; these not only decrease anti-tumour immune responses, but also stimulate tumour growth, angiogenesis and metastasis. [14][15][16] The important role of inflammation in tumour progression comes from the efficacy of long-term and regular use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin in the prevention and treatment of colorectal, breast and other cancers.…”

Section: Derived Suppressor Cells (Mdscs) and Regulatory T Cells (Tregs)mentioning

confidence: 99%

“…The numerous communications between tumour cells and TILs by secreting of cytokines, chemokines, develop chronic inflammation and induce pre‐metastatic niche formation . Tumour‐associated macrophages (TAMs), neutrophils, myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main types of the TILs in the tumour microenvironment during chronic inflammation; these not only decrease anti‐tumour immune responses, but also stimulate tumour growth, angiogenesis and metastasis . The important role of inflammation in tumour progression comes from the efficacy of long‐term and regular use of non‐steroidal anti‐inflammatory drugs (NSAIDs), such as ibuprofen and aspirin in the prevention and treatment of colorectal, breast and other cancers .…”

Section: Introductionmentioning

confidence: 99%

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

Kashefi

Omranipour

Mahmoodzadeh

et al. 2019

Clin Exp Pharma Physio

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Summary Following the potent efficacy of β‐D‐Mannuronic acid in a breast cancer murine model, we evaluated the efficacy of this novel non‐steroidal anti‐inflammatory drug in breast cancer patients in the present clinical trial. The study was an 8‐week randomized, controlled, phase II clinical trial (IRCT: 2017012213739N7 (in 48 pre‐surgical breast cancer patients. Patients who had breast cancer at early stage, with invasive ductal carcinoma, were placed on a waiting‐list for surgery and were allocated to the study. β‐D‐Mannuronic was administrated at a dose of two capsules (1000 mg/d) orally during a period of 8 weeks. The end point of this study was when the patients were admitted for surgery. Moreover, the patients' well‐being status was followed up on for safety. There were no statistically significant differences between treatment and non‐treatment groups at baseline. β‐D‐Mannuronic acid therapy, from 20 patients, showed that in one patient (5%) tumour size was decreased; in five patients (25%) tumour growth was stopped; and in 14 patients (70%) the growth rate in the treatment group did not show significant change, compared to the non‐treatment group. Evaluation of two tumour markers (carcinoembryonic antigen and cancer antigen 15‐3) showed that there was no significant difference between before and after treatment. Although the use of some non‐steroidal anti‐inflammatory drugs in a long time period has shown a prophylactic effect in breast cancer, their therapeutic efficacy in a short time period is unknown, whereas treatment with β‐D‐Mannuronic acid during 8 weeks could show 30% therapeutic effects in pre‐surgical breast cancer patients.

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The Skewed Balance Between Tregs and Th17 in Chronic Lymphocytic Leukemia

Cited by 27 publications

References 146 publications

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

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

Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes

A randomized, controlled, phase II clinical trial of β‐D‐mannuronic acid (M2000) in pre‐surgical breast cancer patients at early stage (T1‐T2)

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