Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells

Ersvær, Elisabeth; Liseth, Knut; Skavland, Jørn; Gjertsen, Bjørn Tore; Bruserud, Øystein

doi:10.1186/1471-2172-11-38

Cited by 66 publications

(59 citation statements)

References 40 publications

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“…91 ) and T-cell chemotactic cytokines 20,92 . Surprisingly, the levels of circulating Th17 cells were not confirmed to be increased in untreated AML patients 93 , which is in contrast to a previous study 94 , possibly due to different mean age of patients enrolled. On the other hand, Th17 cells are not depleted during conventional chemotherapy and circulating Th17 cells can be detected even in periods of severe chemotherapy-induced lymphopenia 93 , so that suf-ficient pre-transplant levels of Th17 cells may be expected.…”

Section: Cytokines In Allogeneic Bone Marrow Transplantationcontrasting

confidence: 55%

“…These observations suggest that Th17 cells are important in GvHD development. As the IL-17 itself has only minor anti-proliferative effect on AML blasts, which was observed only in a minority of patients 93 , its role seems to be initially in immunomodulation. The results mentioned above indicate, that Th17 cells enhancement should be considered at high risk of AML relapse with no clinical GvHD, whereas Th17 cells inhibition or depletion may be useful in treatment of excessive GvHD.…”

Section: Cytokines In Allogeneic Bone Marrow Transplantationmentioning

confidence: 99%

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The role of cytokines in acute myeloid leukemia: A systematic review

Kupsa¹,

Horáček²,

Jebavý³

2012

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Acute myeloid leukemia (AML) shows a high degree of heterogeneity owing to a variety of mutations and the mechanisms of leukemogenesis. This heterogeneity is often not reflected in standard treatment approaches which while providing predictable outcomes in the majority of patients fail in particular cases even with high-dose multiagent chemotherapy regimens. Further, the unselective effect of chemotherapy leads to high treatment-related toxicity and the enormous risk of infection during prolonged pancytopenia, preventing further dose escalation. Objectives. Cytokines play a role in leukemogenesis, AML cell persistence and treatment outcome. In this review we highlight cytokine dependent mechanisms essential for AML cell survival and the role of single cytokines in leukemogenesis and allogeneic transplantation-related phenomena. Cytokine-related mechanisms of leukemogenesis, AML cell persistence and resistance to chemotherapy are complex. Modulation of the cytokine network can disrupt signalling pathway activation and overcome the high resistance to treatment. It may also increase the selectivity of AML treatment, reduce the overall treatment-related toxicity and improve outcomes of AML treatment in all age groups of patients. Conclusions. This review provides a deeper insight into these processes with focus on the most vulnerable step. Special attention is paid to the possibility of selective influence on defined cell populations for therapeutic target. We believe that modulating cytokine-dependent processes in AML is an approach that could be included in standard chemotherapeutic regimens for improving overall treatment outcome.

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Section: Cytokines In Allogeneic Bone Marrow Transplantationcontrasting

confidence: 55%

Section: Cytokines In Allogeneic Bone Marrow Transplantationmentioning

confidence: 99%

The role of cytokines in acute myeloid leukemia: A systematic review

Kupsa¹,

Horáček²,

Jebavý³

2012

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…35, [74][75][76][77] Szczepanski et al demonstrated that 31 AML patients had a greater CD4 ϩ CD25 hi Treg percentage in PB at diagnosis compared with healthy control patients. 35 Tregs from patients with These studies revealed that patients with AML had higher Treg levels compared with HC.…”

Section: Nontransplantation Studiesmentioning

confidence: 99%

Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

Üstün

Miller

Munn

et al. 2011

Blood

174

149

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IntroductionCurrent treatments for acute myelogenous leukemia (AML) have not changed for several decades and have not resulted in satisfactory outcomes. Modulating the immune system may improve survival in patients with AML because the immune system is highly active against leukemic cells. The most compelling evidence for an antileukemic immune effect is seen in recipients of allogeneic hematopoietic stem cell transplantation (alloHCT). 1,2 Donor natural killer (NK) cells, ␥␦ T cells, and cytotoxic T lymphocytes (CTLs) kill leukemic cells after alloHCT. 2,3 Donor lymphocyte infusions (DLIs) can induce modest and often transient responses in patients with AML who relapse after transplantation. 1,4 Conversely, patients with AML have dysfunctional T cells and NK cells at diagnosis 5,6 as well as a greater frequency of immature NK cells during first complete remission (CR). 7 An emerging body of evidence demonstrates that these functional abnormalities are at least in part induced by the tumor itself. For example, direct contact between leukemic cells and NK cells induces a loss or decrease in natural cytotoxicity receptors on NK cells (NCR dull) , 8 a phenotype associated with poor overall survival (OS). Another example is seen with defective or immature dendritic cells (DCs). Defective DCs are found in the peripheral blood (PB) of patients with AML and can induce tolerance toward leukemic cells. 9 NK cells, which are deficient in AML, are at least partly responsible for removing some of these DCs. 10 Taken together, these studies indicate that defects in antileukemic effector cells in patients with AML can contribute to the development and persistence of the disease (Figure 1). In addition to tolerogenic DCs, the authors of recent studies in mice and humans have implicated that immune suppressive regulatory T cells (Tregs) contribute to a defective antileukemic immune response. 11,12 Tregs in the immunosuppressive microenviroment of AML The AML microenviroment is immunosuppressive and antiapoptotic, favoring the survival of malignant hematopoietic cells. 13 The authors of in vitro studies have shown that AML cells secrete factors, which inhibit T-cell activation and proliferation and limit proinflammatory T helper-1 cytokine production. 13,14 This suppressive effect is reversed, however, when Tregs and other T lymphocytes are removed from the microenvironment in vitro, leading to augmented immune responses to AML. 14 In mice, Tregs accumulate in leukemic sites and impede the proliferative and cytolytic capacity of adoptively transferred anti-AML reactive CTLs. 15 Depletion of CD25 (IL-2 receptor ␣-chain)-expressing Tregs by the administration of IL-2 diphtheria toxin results in temporary tumor regression associated with increased CTLs at tumor sites. Combination therapy with IL-2 diphtheria toxin and anti-AML adoptive CTL transfer not only reduces tumor mass but also improves OS in mice. Moreover, mice display resistance to AML cells on rechallenge, implying the development of effective adaptive im...

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“…In previous studies, elevated percentages or levels of Treg cells were reported in the total T-cell population isolated from tumor tissues or peripheral blood in a variety of hematological malignancies, including B-cell non-Hodgkin lymphoma (17), Hodgkin lymphoma (18), chronic lymphocytic leukemia (19)(20)(21), multiple myeloma (22) and AML (5)(6)(7)(8). Treg cells accumulating in the peripheral circulation of AML patients mediate vigorous suppression via IL-10 and TGF-β as well as contact-dependent mechanisms (6).…”

Section: Cytokinementioning

confidence: 99%

“…However, little is known about the pathogenic events leading to the initiation and progression of this disease. Previously, elevated levels of regulatory T (Treg) cells in a variety of hematological malignancies including AML have been reported (5)(6)(7)(8). Patients with a lower Treg cell frequency at diagnosis have a better response to induction chemotherapy and a favorable prognosis (6,8).…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia

Shao

et al. 2012

Oncology Letters

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Abstract. Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and the development of myeloid cells and their precursors in the blood and bone marrow. Interleukin 35 (IL-35), a novel inhibitory cytokine secreted by regulatory T (Treg) cells is a novel potential target used for the therapeutic manipulation of Treg activity in order to treat cancer and autoimmune diseases. To investigate the role and imbalance of Treg-related cytokines in the pathogenesis of AML, we measured the plasma concentration of three Treg-associated cytokines [IL-35, IL-10 and transforming growth factor-β (TGF-β)] and evaluated their clinical relevance. The concentration of IL-35, IL-10 and TGF-β in plasma specimens from 55 patients with AML [27 newly diagnosed (ND) patients and 28 in complete remission (CR)] and 24 controls was analyzed using the enzyme-linked immunosorbent assay method. Significantly higher levels of plasma IL-35 and IL-10 were observed in AML ND patients compared with healthy controls or AML CR patients. IL-10 concentrations were positively correlated with TGF-β, whereas no correlations were found between the other cytokines. IL-10 levels were positively correlated with white blood cell (WBC) and neutrophil (NEU) count but there were no correlations between IL-35 and TGF-β with WBC and NEU count. In conclusion, we demonstrated for the first time that AML ND patients have increased plasma concentrations of IL-35, suggesting that this cytokine is involved in the pathophysiological process of the disease, and that further research is required to address this issue. IntroductionAcute myeloid leukemia (AML) is a life-threatening hematopoietic stem cell neoplasm characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation, frequently resulting in fatal infection, bleeding or organ infiltration, with or without leukocytosis (1-3). The etiology of AML is heterogeneous and complex, but it is widely accepted that both environmental and genetic factors play significant roles in the development of the disease. Immune system disorders have increased our understanding of leukemogenesis (4). However, little is known about the pathogenic events leading to the initiation and progression of this disease. Previously, elevated levels of regulatory T (Treg) cells in a variety of hematological malignancies including AML have been reported (5-8). Patients with a lower Treg cell frequency at diagnosis have a better response to induction chemotherapy and a favorable prognosis (6,8).Treg + Treg cells, which are present in the normal immune system, engage in the maintenance of natural self-tolerance and also the control of immune responses to foreign antigens (9).IL-35, a member of the IL-12 family, is a recently identified heterodimeric cytokine consisting of Epstein-Barr virusinduced gene protein 3 (EBI3) and the p35 subunit of . In contrast to all other known IL-12 family members, which are not expressed by T cells, IL-35...

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Intensive chemotherapy for acute myeloid leukemia differentially affects circulating TC1, TH1, TH17 and TREG cells

Cited by 66 publications

References 40 publications

The role of cytokines in acute myeloid leukemia: A systematic review

The role of cytokines in acute myeloid leukemia: A systematic review

Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia

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