Glucocorticoid-induced Tumor Necrosis Factor Receptor Negatively Regulates Activation of Human Primary Natural Killer (NK) Cells by Blocking Proliferative Signals and Increasing NK Cell Apoptosis

Liu, Baoying; Li, Zhuqing; Mahesh, Sankaranarayana P.; Pantanelli, Seth; Hwang, Frank S.; Siu, Willie O.; Nussenblatt, Robert B.

doi:10.1074/jbc.m708944200

Cited by 61 publications

(69 citation statements)

References 50 publications

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“…However, available data indicate that certain TNFR family members, e.g. GITR which is closely related to 4-1BB, mediate different effects in mice and men and in different cell types, and we demonstrated recently that 4-1BB, alike GITR, inhibits the reactivity of human NK cells [16,[31][32][33][34][35][36]. Of note, Khort and co-workers reported that 4-1BB antibodies may enhance ADCC of NK cells, which were found to express 4-1BB after Fc-receptor triggering.…”

Section: Discussionmentioning

confidence: 87%

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

et al. 2011

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NK cells play an important role in tumor immunosurveillance and largely contribute to the therapeutic success of anti-tumor antibodies like Rituximab. Here, we studied the role of the TNF family member 4-1BB ligand (4-1BBL) during the interaction of NK cells with chronic lymphocytic leukemia (CLL) cells. 4-1BBL was highly expressed on patient B-CLL cells in all 56 investigated cases. Signaling via 4-1BBL following interaction with 4-1BB, which was detected on NK cells of CLL patients but not healthy individuals, led to the release of immunoregulatory cytokines including TNF by CLL cells. CLL patient sera contained elevated levels of TNF and induced 4-1BB upregulation on NK cells, which in turn impaired direct and Rituximab-induced NK-cell reactivity against 4-1BBL-expressing targets. NK-cell reactivity was not only enhanced by blocking the interaction of NK cell-expressed 4-1BB with 4-1BBL expressed by CLL cells, but also by preventing 4-1BB upregulation on NK cells via neutralization of TNF in patient serum with Infliximab. Our data indicate that 4-1BBL mediates NK-cell immunosubversion in CLL, and thus might contribute to the reportedly compromised efficacy of Rituximab to induce NK-cell reactivity in the disease, and that TNF neutralization may serve to enhance the efficacy of Rituximab treatment in CLL.

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Section: Discussionmentioning

confidence: 87%

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

et al. 2011

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“…Our data indicate that RANKL also subverts NK cell immunosurveillance, which can be prevented by the clinically available RANKL Ab Denosumab, at least in RANKL-positive AML cases, which accounted for ∼two-thirds of the patients in our analyses. Notably, species-specific functional differences, which were observed by us and others with regard to the function of other TNFR family members (13,14,27,28,49), were excluded in our study by using human NK cells and primary leukemia cells of AML patients. Our data suggest that modulation of RANK-RANKL interaction may serve to prevent NK cell suppression thereby holding promise to optimize the reactivity of autologous or allogeneic NK cells in AML patients.…”

Section: Discussionmentioning

confidence: 99%

Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

Schmiedel

Nuebling

Steinbacher

et al. 2013

The Journal of Immunology

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The TNF family member receptor activator for NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin are key regulators of bone remodeling but also influence cellular functions of tumor and immune effector cells. In this work, we studied the involvement of RANK–RANKL interaction in NK cell–mediated immunosurveillance of acute myeloid leukemia (AML). Substantial levels of RANKL were found to be expressed on leukemia cells in 53 of 78 (68%) investigated patients. Signaling via RANKL into the leukemia cells stimulated their metabolic activity and induced the release of cytokines involved in AML pathophysiology. In addition, the immunomodulatory factors released by AML cells upon RANKL signaling impaired the anti-leukemia reactivity of NK cells and induced RANK expression, and NK cells of AML patients displayed significantly upregulated RANK expression compared with healthy controls. Treatment of AML cells with the clinically available RANKL Ab Denosumab resulted in enhanced NK cell anti-leukemia reactivity. This was due to both blockade of the release of NK-inhibitory factors by AML cells and prevention of RANK signaling into NK cells. The latter was found to directly impair NK anti-leukemia reactivity with a more pronounced effect on IFN-γ production compared with cytotoxicity. Together, our data unravel a previously unknown function of the RANK–RANKL molecule system in AML pathophysiology as well as NK cell function and suggest that neutralization of RANKL with therapeutic Abs may serve to reinforce NK cell reactivity in leukemia patients.

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“…Stimulation of macrophages with an anti-GITR Ab induces a proinflammatory response (4); however, recent reports have shown that GITR can play an inhibitory role for human NK cell activation (5,6). GITR has also been extensively studied in the context of Tregs and generated much excitement when it was observed that agonistic anti-GITR Ab in cocultures of CD4 + CD25 2 effector T cells and CD4 + CD25 + Tregs caused the abrogation of suppression by Tregs (1, 2).…”

Section: G Lucocorticoid-induced Tnfr-related Protein (Gitr) Is a Memmentioning

confidence: 99%

CD8 T Cell-Intrinsic GITR Is Required for T Cell Clonal Expansion and Mouse Survival following Severe Influenza Infection

Snell

McPherson

Lin

et al. 2010

The Journal of Immunology

115

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Glucocorticoid-induced Tumor Necrosis Factor Receptor Negatively Regulates Activation of Human Primary Natural Killer (NK) Cells by Blocking Proliferative Signals and Increasing NK Cell Apoptosis

Abstract: Glucocorticoid-induced tumor necrosis factor receptor (GITR),

Cited by 61 publications

References 50 publications

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

Receptor Activator for NF-κB Ligand in Acute Myeloid Leukemia: Expression, Function, and Modulation of NK Cell Immunosurveillance

CD8 T Cell-Intrinsic GITR Is Required for T Cell Clonal Expansion and Mouse Survival following Severe Influenza Infection

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