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

Coles, Steven; Gilmour, Marie; Reid, Reiss; Knapper, Steven; Burnett, Alan Kenneth; Man, Stephen; Tonks, Alex; Darley, Richard Lawrence

doi:10.1038/leu.2015.62

Cited by 45 publications

(38 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[11][12][13][14][15] In particular, few studies have tried to unravel the importance of PD-1/programmed cell death ligand 1 (PD-L1) in primary acute myeloid leukemia (AML). [16][17][18][19][20] Bispecific T-cell engaging (BiTE) antibody constructs are a novel class of therapeutic antibodies, which are composed of two single chain variable fragments (scFv), simultaneously targeting a tumor antigen on cancer cells and CD3ε in the T cell receptor complex. BiTE antibody constructs are able to effectively recruit antigen-experienced T cells irrespectively of their specificity.…”

Section: Introductionmentioning

confidence: 99%

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

et al. 2015

View full text Add to dashboard Cite

Bispecific T-cell engagers (BiTEs) are very effective in recruiting and activating T cells. We tested the cytotoxicity of the CD33/CD3 BiTE antibody construct AMG 330 on primary acute myeloid leukemia (AML) cells ex vivo and characterized parameters contributing to antileukemic cytolytic activity. The E:T ratio and the CD33 expression level significantly influenced lysis kinetics in long-term cultures of primary AML cells (n=38). AMG 330 induced T-cell-mediated proinflammatory conditions, favoring the upregulation of immune checkpoints on target and effector cells. Although not constitutively expressed at the time of primary diagnosis (n=123), PD-L1 was strongly upregulated on primary AML cells upon AMG 330 addition to ex vivo cultures (n=27, P<0.0001). This phenomenon was cytokine-driven as the sole addition of interferon (IFN)-γ and tumor necrosis factor-α also induced expression. Through blockade of the PD-1/PD-L1 interaction, AMG 330-mediated lysis (n=9, P=0.03), T-cell proliferation (n=9, P=0.01) and IFN-γ secretion (n=8, P=0.008) were significantly enhanced. The combinatorial approach was most beneficial in settings of protracted AML cell lysis. Taken together, we have characterized a critical resistance mechanism employed by primary AML cells under AMG 330-mediated proinflammatory conditions. Our results support the evaluation of checkpoint molecules in upcoming clinical trials with AMG 330 to enhance BiTE antibody construct-mediated cytotoxicity.

show abstract

Section: Introductionmentioning

confidence: 99%

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

et al. 2015

View full text Add to dashboard Cite

show abstract

“…8 Meanwhile, an inhibitory CD200 receptor (CD200R) is induced by lymphoid cells, ie, natural killer and activated T cells. 9 The dual function of CD200 suggests the existence of an "OC checkpoint," which downregulates immune effector cells. Here, we postulated that this OC checkpoint mechanism may promote immune escape of MM cells, analogous to tumor cells evading immune destruction due to aberrant immune checkpoint pathways.…”

Section: Introductionmentioning

confidence: 99%

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

Acharya

Feng

et al. 2016

Blood

144

135

View full text Add to dashboard Cite

show abstract

“…6 Ligation of PD-1 on T cells in the tumor bed induces an exhausted T-cell phenotype resulting in the loss of activation, expansion and functional capacity of tumor reactive lymphocytes. 45 PD-L1 is strongly expressed by AML cells 3,5,6 and is also expressed by other immunosuppressive elements in the BM microenvironment. 46–48 Defining the mechanisms by which PD-L1 expression is regulated is vital to better understand the evolution of immune dysregulation in AML and as a basis for the design of novel therapies to restore immune function.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 The PD-L1/PD-1 pathway confers a critical negative co-stimulatory signal that induces T-cell exhaustion and supports immune evasion by malignant cells. 3–6 In contrast, antibody blockade of PD-L1/PD-1 signaling results in the reversal of tumor-mediated immune suppression and durable responses in subsets of patients with solid tumors 7–9 and hematological malignancies. 10 Although PD-L1 expression in AML is dynamic, little is known about the mechanism(s) responsible for regulating PD-L1 expression in AML.…”

Section: Introductionmentioning

confidence: 99%

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

et al. 2017

View full text Add to dashboard Cite

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.

show abstract

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

Cited by 45 publications

References 17 publications

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cell-induced immune escape mechanism

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

Contact Info

Product

Resources

About