Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α–TNF Receptor-2 Pathway

Wei, Min; Zhang, Chen; Tian, Tian; Zhang, Teng; Wang, Ruiqing; Han, Fengjiao; Zhong, Chaoqin; Hua, Mingqiang; Ma, Daoxin

doi:10.3389/fimmu.2018.01274

Cited by 45 publications

(33 citation statements)

References 32 publications

(34 reference statements)

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“…The expression of ICOSL was very weak on the murine AML cell line C1498 and treatment with TNF-α 50 ng/ml for 48 h also induced the expression of ICOSL in C1498 cells in vitro (Figure 1D ). Since it has been recognized that the level of TNF-α is elevated in AML patients ( 24 , 25 ), we speculate that the expression of ICOSL on AML cells can be enhanced in vivo . As expected, the expression of ICOSL was increased when C1498 cells were injected intravenously into C57BL/6J mice (Figure 1D ).…”

Section: Resultsmentioning

confidence: 89%

Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

et al. 2018

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CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in bone marrow microenvironment in acute myeloid leukemia (AML). However, little is known about how the tumor environment including tumor cells themselves affects this process. Here we demonstrated that AML cells expressed inducible T-cell costimulator ligand (ICOSL) that can provide costimulation through ICOS for the conversion and expansion of Tregs sustaining high Foxp3 and CD25 expression as well as a suppressive function. TNF-a stimulation up-regulated the expression of ICOSL. Furthermore, both the conversion and expansion of CD4+CD25+Foxp3+ T cells and CD4+ICOS+Foxp3+ T cells were induced by co-culture with AML cells overexpressed ICOSL. CD4+CD25+ICOS+ T cells possessed stronger ability to secrete IL-10 than CD4+CD25+ICOS− T cells. The mechanism by which IL-10 promoted the proliferation of AML cells was dependent on the activation of the Akt, Erk1/2, p38, and Stat3 signaling pathways. Blockade of ICOS signaling using anti-ICOSL antibody impaired the generation of Tregs and retarded the progression of an AML mice model injected with C1498 cells. The expression of ICOSL of patient AML cells and ICOS+ Tregs were found to be predictors for overall survival and disease-free survival in patients with AML, with ICOS+ Treg cell subset being a stronger predictor than total Tregs. These results suggest that ICOSL expression by AML cells may directly drive Treg expansion as a mechanism of immune evasion and ICOS+ Treg cell frequency is a better prognostic predictor in patients with AML.

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Section: Resultsmentioning

confidence: 89%

Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

et al. 2018

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“…It is well-known that the AML microenvironment is mostly enriched in Tregs, which interacts with effector T cells, thus crucially dampening the anti-leukemia immune response and favoring leukemia immunological escape [54,55]. In particular, the role of Tregs in AML is very important for both the characterization of the BM microenvironment composition before chemotherapy and the prediction of response to chemotherapy [56][57][58][59]. Indeed, as compared to healthy individuals, AML patients at diagnosis may have higher numbers of Tregs, whose frequency is directly correlated with response to chemotherapy [57,60], and a rapid turnover of Tregs after chemotherapy has been demonstrated in AML patients [58].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the role of Tregs in AML is very important for both the characterization of the BM microenvironment composition before chemotherapy and the prediction of response to chemotherapy [56][57][58][59]. Indeed, as compared to healthy individuals, AML patients at diagnosis may have higher numbers of Tregs, whose frequency is directly correlated with response to chemotherapy [57,60], and a rapid turnover of Tregs after chemotherapy has been demonstrated in AML patients [58]. Our group has recently addressed the mechanisms by which DNR and Ara-C may contribute to modify the immune response in AML patients and in a mouse model of AML [1].…”

Section: Discussionmentioning

confidence: 99%

A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals Contrasting Immunogenic Effects of Etoposide and Fludarabine

Očadlíková

Iannarone

Redavid

et al. 2020

IJMS

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Background: Recent evidence demonstrated that the treatment of acute myeloid leukemia (AML) cells with daunorubicin (DNR) but not cytarabine (Ara-C) results in immunogenic cell death (ICD). In the clinical setting, chemotherapy including anthracyclines and Ara-C remains a gold standard for AML treatment. In the last decade, etoposide (Eto) and fludarabine (Flu) have been added to the standard treatment for AML to potentiate its therapeutic effect and have been tested in many trials. Very little data are available about the ability of these drugs to induce ICD. Methods: AML cells were treated with all four drugs. Calreticulin and heat shock protein 70/90 translocation, non-histone chromatin-binding protein high mobility group box 1 and adenosine triphosphate release were evaluated. The treated cells were pulsed into dendritic cells (DCs) and used for in vitro immunological tests. Results: Flu and Ara-C had no capacity to induce ICD-related events. Interestingly, Eto was comparable to DNR in inducing all ICD events, resulting in DC maturation. Moreover, Flu was significantly more potent in inducing suppressive T regulatory cells compared to other drugs. Conclusions: Our results indicate a novel and until now poorly investigated feature of antineoplastic drugs commonly used for AML treatment, based on their different immunogenic potential.

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“…They act both directly through anti-inflammatory cytokine secretion and contact dependent suppression and indirectly, by interfering with the activation status of antigen presenting cells (62). The AML microenvironment favors the expansion of Tregs (37,(63)(64)(65). Expression of inducible T cell co-stimulator ligand (ICOSL) on AML blasts stimulates T cells through inducible T cell costimulator (ICOS), leading to differentiation to Treg phenotype and expansion of the Treg subset (66).…”

Section: Regulatory T Cellsmentioning

confidence: 99%

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

Epperly

Velasquez

2020

Front. Oncol.

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Chimeric antigen receptor (CAR) T cells targeting CD19 have been successful treating patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) and B cell lymphomas. However, relapse after CAR T cell therapy is still a challenge. In addition, preclinical and early clinical studies targeting acute myeloid leukemia (AML) have not been as successful. This can be attributed in part to the presence of an AML microenvironment that has a dampening effect on the antitumor activity of CAR T cells. The AML microenvironment includes cellular interactions, soluble environmental factors, and structural components. Suppressive immune cells including myeloid derived suppressor cells and regulatory T cells are known to inhibit T cell function. Environmental factors contributing to T cell exhaustion, including immune checkpoints, anti-inflammatory cytokines, chemokines, and metabolic alterations, impact T cell activity, persistence, and localization. Lastly, structural factors of the bone marrow niche, secondary lymphoid organs, and extramedullary sites provide opportunities for CAR T cell evasion by AML blasts, contributing to treatment resistance and relapse. In this review we discuss the effect of the AML microenvironment on CAR T cell function. We highlight opportunities to enhance CAR T cell efficacy for AML through manipulating, targeting, and evading the anti-inflammatory leukemic microenvironment.

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Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α–TNF Receptor-2 Pathway

Cited by 45 publications

References 32 publications

Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

Acute Myeloid Leukemia Cells Express ICOS Ligand to Promote the Expansion of Regulatory T Cells

A Screening of Antineoplastic Drugs for Acute Myeloid Leukemia Reveals Contrasting Immunogenic Effects of Etoposide and Fludarabine

A Bump in the Road: How the Hostile AML Microenvironment Affects CAR T Cell Therapy

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