Acute Lymphoblastic Leukemia and Regulatory T cells: Biomarkers and Immunopathogenesis (original) (raw)
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Immunology, 2014
Regulatory T (Treg) cells act to suppress activation of the immune system and thereby maintain immunological homeostasis and tolerance to selfantigens. The frequency and suppressing activity of Treg cells in general are high in different malignancies. We wanted to identify the role and regulation of CD4 + CD25 + FoxP3 + Treg cells in B-cell acute lymphoblastic leukaemia (B-ALL). We have included patients at diagnosis (n = 54), patients in clinical remission (n = 32) and normal healthy individuals (n = 35). These diagnosed patients demonstrated a lower number of CD4 + CD25 + cells co-expressing a higher level of FoxP3, interleukin-10, transforming growth factor-b and CD152/CTLA-4 than the normal population. Treg cells from patients showed a higher suppressive capability on CD4 + CD25 À responder T (Tresp) cells than normal. The frequency and immunosuppressive potential of CD4 + CD25 + FoxP3 + Treg cells became high with the progression of malignancy in BALL. Relative distribution of Tresp and Treg cells was only~5 : 1 in BALL but~35 : 1 in normal healthy individuals, further confirming the elevated immunosuppression in patients. A co-culture study at these definite ex vivo ratios, indicated that Treg cells from BALL patients exhibited higher immunosuppression than Treg cells from normal healthy individuals. After chemotherapy using the MCP841 protocol, the frequency of CD4 + CD25 + cells was gradually enhanced with the reduction of FoxP3, interleukin-10 positivity corresponded with disease presentation, indicating reduced immunosuppression. Taken together, our study indicated that the CD4 + CD25 + FoxP3 + Treg cells played an important role in immunosuppression, resulting in a positive disease-correlation in these patients. To the best of our knowledge, this is the first detailed report on the frequency, regulation and functionality of Treg cells in BALL .
Clinical Cancer Research, 2009
Purpose: Regulatory CD4+CD25highFoxp3+ T cells (Treg) control peripheral immune tolerance. Patients with cancer, including those with hematologic malignancies, have elevated numbers of Treg in the peripheral circulation and in tumor tissues. However, mechanisms of suppression and clinical significance of Treg, especially in patients with acute myelogenous leukemia (AML), has not been well defined. Experimental Design: We prospectively evaluated the phenotype, function, and mechanisms of suppression used by Treg in newly diagnosed untreated AML patients. The relationship between the frequency of circulating Treg and the disease status as well as treatment outcome was also evaluated. Results: The percentage of circulating Treg was higher (P < 0.0001) and their phenotype was distinct in AML patients relative to normal controls. Suppression mediated by Treg coincubated with proliferating autologous responder cells was also higher (P < 0.001) in AML than that mediated by control Tr...
Intracellular cytokine profile of T cells from children with acute lymphoblastic leukemia
Cancer Immunology, Immunotherapy, 2000
Purpose: During an ongoing immune response, cytokines produced by T helper types 1 (Th1) and 2 (Th2) together with T cytotoxic types 1 (Tc1) and 2 (Tc2) are critical to the eectiveness of that response. Dysregulated expansion of one or the other subset may contribute to the impaired function of the T-cell-mediated immune system in cancer patients. In the present study we have investigated whether such dysregulation might exist in children with acute lymphoblastic leukemia (ALL). Methods: We analyzed 61 blood samples from 45 children with B cell precursor ALL and 16 healthy children. Interleukin(IL)-2, IL-4, and interferon c (IFNc) production of their respective puri®ed CD4 + and CD8 + T cells were assessed at the single-cell level by intracellular-cytokine-staining¯ow cytometry. Results: At the time of diagnosis, IL-2-producing cell populations in CD4 + and CD8 + T cells were reduced below the normal range in 31 of 44 (70.5%) and 23 of 38 (60.5%) cases respectively. Similarly, IFNc-producing cell populations in CD4 + and CD8 + T cells decreased in 17 of 44 (38.6%) and 18 of 38 (47.4%) cases respectively.
Immunopharmacology and immunotoxicology, 2018
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The precise mechanism behind the relapse in this disease is not clearly known. One possible mechanism could be the accumulation of immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (T) which we and others have reported to mediate suppression of anti-tumor immune responses. In this study, we aimed to analyze the numbers of these cells in a population of B-ALL pediatric patients. Peripheral blood samples withdrawn from B-ALL pediatric patients (n = 45 before, during and after the induction phase of chemotherapy. Using multi parametric flow cytometric analysis. MDSCs were identified as LinHLA-DRCD33CD11b; and Tcells were defined as CD4CD25CD127. Early diagnosed B-ALL patients showed significant increases in the numbers of MDSCs and Tas compared to healthy volunteers. During induction of chemotherapy, however, the patients showed higher and lower numbers o...
Iranian journal of immunology : IJI, 2020
BACKGROUND Drugs used in cancer treatment specifically kill T regulatory cells. OBJECTIVE To determine different phenotypes of T regulatory cells during the maintenance phase chemotherapy for pediatric acute lymphoblastic leukemia (ALL). MATERIALS We evaluated the percentages of regulatory T cells by flow cytometry. Soluble CTLA-4 (sCTLA-4) in plasma was evaluated by ELISA assay. RESULTS Increased percentages of CD4+CD25+ T cells, CD4+CD39+ T cells, CD4+Foxp3+ T cells, and CD4+CD25High T cells were observed in children with ALL in comparison to healthy controls. In addition, the ALL patients with >12 months of therapy showed increased CD4+CD39+ T cells compared to the ALL patients with ≤12 months and healthy controls. Similarly, the CD4+CD25+ T cells and CD4+Foxp3+ T cells increased according to maintenance therapy time. CONCLUSION Our results showed increased percentages of regulatory T cells in pediatric ALL patients despite chemotherapy, which might be compromising the anti-le...
Children with acute lymphoblastic leukemia show high numbers of CD4+ and CD8+ T‑cells.pdf
Background: Acute lymphoblastic leukemia (ALL) is considered as one of the most common cancer in pediatric malignancies. Among ALL, B-cell Acute Lymphoblastic Leukemia (B-ALL) represents 80% to 85% of the childhood ALL. Problem: Although anti B‑ALL chemotherapy kill B‑ALL, it associates with alteration in the numbers of CD4+ and CD8+ T‑cells, and thus impacts the overall immunity. Aim: To evaluate the impact of anti B‑ALL on the numbers of CD4+ and CD8+ T‑cells in correlation to the numbers of CD10+ B cells in B‑ALL pediatric patients. Materials and Methods: Peripheral blood samples were drawn from previously diagnosed B‑ALL before (n = 10 cases) and after (n = 10 cases) chemotherapy as well as from healthy controls (n = 10 cases). The numbers of CD4+, CD8+ T‑cells and CD10+ B cells were measured in these samples by flow cytometry. Results: As expected, the numbers of CD10+ B‑cells were increased in B‑ALL patients before chemotherapy which were associated with increases in the numbers of CD4+ and CD8+ T‑cells. Chemotherapy of B‑ALL patients, during the induction phase, induced dramatic decreases in the numbers of CD10+ B cells, which were associated with decreases in the numbers of CD4+ and CD8+ T‑cells. Tin spite of this alteration, the ratio of CD4/CD8 in B‑ALL patients were remained similar before and after chemotherapy as compared to those in healthy controls. Conclusion: Anti B‑ALL chemotherapy induces alterations in the frequencies of T‑cell subsets. Given the importance of these cells in anti‑tumor immunity, our data may lead to further studies to investigate the different subsets of these cells, in particular regulatory T‑cells. Key words: B‑acute lymphoblastic leukemia, B‑ALL, B‑cells, cancer, CD10, CD4, CD8, chemotherapy, T‑cells, Tregs
Cancer Immunology, Immunotherapy, 2017
cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T reg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T reg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T regs in later treatment cycles and a short T reg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T regs that may be targeted for improved anti-leukemic efficiency. Keywords Acute myeloid leukemia • Regulatory T cells • IL-2 • Immunotherapy Abbreviations Allo-SCT Allogeneic stem cell transplant AML Acute myeloid leukemia C1D1 Cycle 1, day 1 C1D21 Cycle 1, day 21 C3D1 Cycle 3, day 1 C3D21 Cycle 3, day 21 CR Complete remission GvHD Graft-versus-host disease HDC Histamine dihydrochloride iT regs Induced regulatory T cells LFS Leukemia-free survival NOX2 Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 nT regs Natural regulatory T cells OS Overall survival qPCR Quantitative PCR ROS Reactive oxygen species T cons Conventional T cells Abstract Regulatory T cells (T regs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the postconsolidation phase. This study aimed at defining the features, function and dynamics of Foxp3 + CD25 high CD4 + T regs during immunotherapy and to determine the potential impact of T regs on relapse risk and survival. We observed a pronounced increase in T reg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T regs resembled thymic-derived natural T regs (nT regs), showed augmented expression of CTLA-4 and suppressed the cell Electronic supplementary material The online version of this article (
Journal of translational medicine, 2018
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. 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-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test. In all CLL samples, we found a significant increase in the frequency of IL-10-sec...
Cancer immunology research, 2016
The regulatory T cells (Tregs) with the most potent immunosuppressive activity are the effector regulatory T cells (eTregs) with a CD45RA-Foxp3++CCR4+ phenotype. Adult T cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here we present two ATL cases that responded to mogamulizumab, but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the TCR revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply t...