Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells

Coles, Steven; Hills, Robert Kerrin; Wang, Edward Chung Yern; Burnett, Alan Kenneth; Man, Stephen; Darley, Richard Lawrence; Tonks, Alex

doi:10.1038/leu.2012.75

Cited by 53 publications

(41 citation statements)

References 17 publications

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“…Preconditioning with lymphocyte depletion enhances homeostatic proliferation and depletes host Treg cells. However, it also carries along significant to promote the expansion of Treg cells, and CD200 blockade significantly decreases Treg cell numbers (6,7,49). Ibrutinib treatment of CLL patients dramatically reduced the frequency of malignant B10Pro cells, which can express IL-10 after prolonged in vitro stimulation, and similar findings with acalabrutinib suggest this is a BTK-dependent effect.…”

Section: Foxp3supporting

confidence: 57%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

297

343

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BACKGROUND.Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS.Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8 + T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4 + T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.

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Section: Foxp3supporting

confidence: 57%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

297

343

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“…A promising approach is to augment the antitumor immune response in these patients; however, it is well established that overexpression of immunosuppressive molecules such as CD200 on the surface of AML cells directly suppresses the antitumor response. [2][3][4] Nevertheless, blocking CD200:CD200R, only partially restores T-cell activity, suggesting that alternative immunosuppressive mechanisms need to be explored if the antitumor response in AML is to be optimally exploited. 5 Recently, promising clinical outcomes using humanized antibodies targeting PD-1 have been reported for melanoma and even for non-small cell lung cancer.…”

mentioning

confidence: 94%

“…AML blast cells were identified through CD45/CD34 bivariate analysis as previously described. 2 The data illustrate a positive correlation between CD200 and PD-L1 protein expression (normalized mean fluorescence intensity; MFI) 2 whether CD200:CD200R stimulation was directly capable of mediating PD-1 up-regulation on target CD8 + T cells. We carried out a refined coculture assay in which a CD8 + T cell clone (7E7) 13 was incubated with CD200 + or CD200 -K562 cells.…”

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confidence: 96%

The immunosuppressive ligands PD-L1 and CD200 are linked in AML T-cell immunosuppression: identification of a new immunotherapeutic synapse

et al. 2015

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“…The presence of high Treg levels in patients with AML correlate with poor clinical outcomes (9). This increase of Tregs has been attributed to AML blasts, which increase the frequency of Tregs through a variety of mechanisms including those linked to the effects of B7-H1 (10), indoleamine 2,3-dioxygenase (11), and CD200 (12). Depletion of Tregs in vivo using an IL-2 diphtheria toxin in a murine AML model resulted in an enhancement of the frequency of CTLs and a reduced tumor burden (13).…”

Section: Introductionmentioning

confidence: 99%

Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

Govindaraj

Tan

Walker

et al. 2014

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) provides an environment that enables immune suppression, resulting in functionally defective effector T cells; regulatory T cells (Treg) are significant contributors to the impaired antitumor immune response. As TNF is present at high levels in AML and TNF receptor-2 (TNFR2)-expressing Tregs identify highly functional Tregs, we examine the hypothesis that TNFR2þ Tregs are a relevant Treg subset in this cancer. We also determine the effect of the novel combinatorial therapy of the demethylating agent, azacitidine with the histone deacetylase inhibitor, panobinostat on Tregs, particularly TNFR2 þ Tregs.Experimental Design: Thirty healthy donors and 14 patients with AML were enrolled in this study. Patients were treated with azacitidine and panobinostat for 28-day cycles. The frequency and functional relevance of TNFR2 þ Tregs were analyzed subsequently.

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Increased CD200 expression in acute myeloid leukemia is linked with an increased frequency of FoxP3+ regulatory T cells

Cited by 53 publications

References 17 publications

Ibrutinib treatment improves T cell number and function in CLL patients

Ibrutinib treatment improves T cell number and function in CLL patients

The immunosuppressive ligands PD-L1 and CD200 are linked in AML T-cell immunosuppression: identification of a new immunotherapeutic synapse

Reducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients

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