Regulatory T cells in egyptian acute myeloid leukemia patients

Abstract An elevated frequency of CD4+CD25high regulatory T cells (Treg) has been reported in the peripheral blood in patients with various solid tumors and hematologic malignancies. Although the increase in Treg seems to be a characteristic feature of most tumors, the functional role of Treg and the mechanisms of suppression, especially in patients with hematologic malignancies, have been less well defined. We investigated Treg-mediated suppression and the responsible mechanisms in thirty newly diagnosed acute myeloid leukemia (AML) patients prior to any treatment and twenty five healthy donors (NC). The percentage of circulating CD4+ CD25high Treg was higher (p <0.0001) in the AML patients (4.5 ±0.2%, range 1.7–8.2%) compared to NC (1.5 ± 0.08%, range 0.9–3.1 %). To evaluate the suppressive function, CD4+CD25high T cells (S) were co-cultured with sorted, CFSE-labeled autologous CD4+CD25high T cells (R) at different S/R ratios. Suppression mediated by Treg co-incubated with proliferating autologous responders was significantly higher (p<0.001) in AML than that mediated by control Treg. To evaluate the role of cytokines produced by Treg in suppression and a need for cell-to- cell contact, transwell analysis of S/R co-cultures was performed. Co-incubation in the presence of transwell inserts (TRI) resulted in significant reduction of suppression (p<0.05), and the addition of neutralizing antibodies to IL-10 and TGF-β1 in the presence of TRI further decreased suppression mediated by Treg. These data suggest that both immunoinhibitory cytokine production and cell-to-cell contact are necessary for suppression. To explore other potential mechanisms of Treg suppression, we evaluated the expression by Treg of ectonucleotidases CD39 and CD73 and the capability of Treg to produce adenosine. CD4+CD25high T cells of AML patients had higher expression (p<0.01) of CD39 and more efficiently hydrolyzed ATP to adenosine relative to Treg in NC. These data indicate that various mechanisms of suppression may be utilized by Treg in patients with AML. The increase frequency of Treg mediating potent suppression by various mechanisms is likely to play a role in host anti-tumor immune responses. Therefore, modulation of the frequency and functions of Treg might provide new immunotherapeutic approaches in AML.

Download Full-text

Faculty Opinions recommendation of Engineered type 1 regulatory T cells designed for clinical use kill primary pediatric acute myeloid leukemia cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738855564.793589480 ◽

2021 ◽

Author(s):

Jan Starý ◽

Justina Krotka

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Regulatory T Cells ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Clinical Use ◽

Pediatric Acute Myeloid Leukemia ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

Download Full-text

Expression of CD25+ Cell Subsets after Induction Chemotherapy in Adult Patients with Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v106.11.4597.4597 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4597-4597

Author(s):

Woo-Sung Min ◽

Hee-Je Kim ◽

Young Choi ◽

Sung-Yong Kim ◽

Ki-Sung Eom ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Regulatory T Cells ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Early Period ◽

Adult Patients ◽

Cd4 Cell ◽

Lower Expression ◽

Acute Myeloid

Abstract An attempt was made to correlate clinical outcomes with specific patterns of the expression of CD25+ cells after induction chemotherapy (IC) in adult patients with acute myeloid leukemia (AML). Seventy-five newly diagnosed AML patients received the same initial IC and serial bone marrow (BM)- or peripheral blood (PB)-samples were taken. The gated CD45/CD25/CD4 cell populations were used to compare for the intensity of immunophenotypic signals and the different cell subsets, according to the treatment timeline. As one of the best predictive prognostic parameters, patients who responded poorly to IC showed exceptionally higher levels of PB CD45+CD25+ cells on days 7 (P=0.002) and 21 (P=0.05) post-IC. The results of patients in complete remission (CR)(n=61), as well as those of the patients who showed continuous CR, showed relatively lower levels of PB CD45+CD25+ and higher CD4+CD25+ regulatory T cells in the steady PB after the standard IC, which was accurately discernible in every patient and in normal healthy individuals (n=21). We found considerably lower expression levels of BM/PB CD4+CD25+ regulatory T cells in the patients. These results suggest that this tool can be used to predict the outcome of adult AML patients at an early period in treatment.

Download Full-text

CD4+ CD25high Regulatory T Cells in Newly Diagnosed Patients with Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.2835.2835 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2835-2835

Author(s):

Miroslaw J. Szczepanski ◽

Laura Strauss ◽

Malgorzata Czystowska ◽

Marta Szajnik ◽

Ann Welsh ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Regulatory T Cells ◽

Myeloid Leukemia ◽

Fas Ligand ◽

Hematologic Malignancies ◽

Newly Diagnosed ◽

Therapeutic Implications ◽

Healthy Donors ◽

Acute Myeloid

Abstract Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. Increasing evidence supports the existence of elevated numbers of regulatory T cells in cancer patients. Although the increase of T cells seems to be a characteristic feature in most tumors the functional role of Treg, especially in patients with hematologic malignancies, has been less well defined. Mutlicolor flow cytomerty was used to investigated the frequency and phenotype of CD4+ CD25high T cells in the peripheral blood of thirty seven newly diagnosed acute myeloid leukemia (AML) patients (prior to any treatment) and thirty one healthy donors. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4+CD25− T cells activated with an anti-CD3 antibody as responders. The percentage of circulating CD4+ CD25high Treg was higher (p < 0.0001) in the AML patients (2.9 ± 0.3%, range 0.1–7%) compared to healthy donors (0.4 ± 0.02%, range 0.1–1%). Percentages of T reg expressing Foxp3, CTLA-4, CD45 RO, Fas ligand (CD95) and GITR were significantly elevated in the circulation of AML patients compared to healthy donors: Foxp3 60vs32% p<0.001, CTLA-4 47vs21% p<0.01, CD45 RO 81vs53% p<0.002, Fas ligand 23vs4% p<0.001, GITR 65vs25% p<0.001. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p<0.001) in AML than that mediated by control T reg (75 ± 6% vs 12% ± 4%). These results indicate that T reg accumulate in the periphery of patients with AML and mediate vigorous suppression. Modulation of the Treg suppressive activity, especially during the post-induction period, in AML patients may have therapeutic implications.

Download Full-text

Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia

Blood ◽

10.1182/blood-2010-03-275446 ◽

2010 ◽

Vol 116 (14) ◽

pp. 2484-2493 ◽

Cited By ~ 167

Author(s):

Qing Zhou ◽

Meghan E. Munger ◽

Steven L. Highfill ◽

Jakub Tolar ◽

Brenda J. Weigel ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Acute Myeloid Leukemia ◽

Regulatory T Cells ◽

Myeloid Leukemia ◽

Antibody Treatment ◽

T Effector Cells ◽

Treg Depletion ◽

Acute Myeloid

Abstract Tumor-induced immune defects can weaken host immune response and permit tumor cell growth. In a systemic model of murine acute myeloid leukemia (AML), tumor progression resulted in increased regulatory T cells (Treg) and elevation of program death-1 (PD-1) expression on CD8+ cytotoxic T cells (CTLs) at the tumor site. PD-1 knockout mice were more resistant to AML despite the presence of similar percentage of Tregs compared with wild type. In vitro, intact Treg suppression of CD8+ T-cell responses was dependent on PD-1 expression by T cells and Tregs and PD-L1 expression by antigen-presenting cells. In vivo, the function of adoptively transferred AML-reactive CTLs was reduced by AML-associated Tregs. Anti–PD-L1 monoclonal antibody treatment increased the proliferation and function of CTLs at tumor sites, reduced AML tumor burden, and resulted in long-term survivors. Treg depletion followed by PD-1/PD-L1 blockade showed superior efficacy for eradication of established AML. These data demonstrated that interaction between PD-1 and PD-L1 can facilitate Treg-induced suppression of T-effector cells and dampen the antitumor immune response. PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease.

Download Full-text