Fc-dependent expression of CD137 on human NK cells: insights into “agonistic” effects of anti-CD137 monoclonal antibodies

Lin, Wei; Voskens, Caroline J.; Zhang, Xiaoyu; Schindler, Daniel; Wood, Aaron; Burch, Erin; Wei, Yadong; Chen, Lieping; Tian, Guo‐Liang; Tamada, Koji; Wang, Lai-Xi; Schulze, Dan H.; Mann, Dean L.; Strome, Scott E.

doi:10.1182/blood-2007-11-122465

Cited by 109 publications

(93 citation statements)

References 29 publications

(36 reference statements)

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“…Since NK cells upregulate 4-1BB upon activation [14,16] we next determined the expression of 4-1BB and the activation marker CD69 on NK cells of our CLL patients. While being virtually absent on NK cells of 10 healthy donors, significantly (po0.05, Student's t-test) enhanced expression of 4-1BB and CD69 (notably without a correlation between the two molecules) was observed on NK cells of the CLL patients, and only in one of the 54 CLL cases available for analysis no relevant NK 4-1BB expression was detected ( Fig.…”

Section: -1bb On Cll Patient Nk Cells Impairs Nk Reactivity Upon Intmentioning

confidence: 99%

“…4-1BB (TNFRSF9, CD137) is well known as an inducible costimulatory receptor on T cells and potently stimulates anti-tumor immunity in mice [12,13]. Besides T cells, 4-1BB is functionally expressed on activated NK cells [14][15][16][17]. Of note, interaction of 4-1BB with its ligand (4-1BBL) not only induces signaling via the receptor, but also results in transduction of signals into the ligand-expressing cell (bidirectional signaling).…”

Section: Introductionmentioning

confidence: 99%

“…Such signals via 4-1BBL influence proliferation, survival and cytokine secretion of various healthy and malignant cell types [18]. As (i) Fc-receptor triggering was recently reported to enhance 4-1BB expression on NK cells [14,19], (ii) 4-1BBL has been reported to be functionally expressed on healthy B cells and tumor cell lines of lymphoid origin [20], and (iii) we recently found that 4-1BB/4-1BBL interaction impairs the reactivity of human NK cells against acute myeloid leukemia (AML) cells [16] we here studied the expression of 4-1BBL in CLL and its influence on direct and Rituximabinduced NK-cell reactivity.…”

Section: Introductionmentioning

confidence: 99%

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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: -1bb On Cll Patient Nk Cells Impairs Nk Reactivity Upon Intmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…Recently, it was shown that human NK cells upon Fc-receptor triggering, such as the interaction with antibody-bound tumor cells, upregulate the inducible costimultory molecule, CD137 (11). Once induced to express CD137, we hypothesize that the killing function of these activated NK cells can be enhanced by their exposure to an agonistic mAb against CD137, leading to improved anti-tumor activity.…”

Section: Trastuzumab a Monoclonal Antibody (Mab) Targeting Her-2/neumentioning

confidence: 99%

Augmenting Trastuzumab Therapy Against Breast Cancer Through Selective Activation of NK Cells

Kohrt¹

2012

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“…4-1BB (CD137) is a costimulatory receptor expressed on T, B and NK cells 7 whose expression is triggered by engagement of the Fc receptors on the NK cell surface, as during antibody-dependent cell cytotoxicity (ADCC). 8 Consequently, the engagement of CD137 increases cetuximab-, rituximab-, and trastuzumab-dependent NK cell cytotoxic function in different cancer models. [9][10][11] NK cell activation is dominantly suppressed if the inhibitory NKR bind to MHC class I molecules on target cells.…”

Section: Introductionmentioning

confidence: 99%

Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes

et al. 2016

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CD245 is a human surface antigen expressed on peripheral blood lymphocytes, initially delineated by two monoclonal antibodies DY12 and DY35. Until now, CD245 molecular and functional characteristics remained largely unknown. We combined immunological and proteomic approaches and identified CD245 as the unconventional myosin 18A, a highly conserved motor enzyme reported as a receptor for the surfactant protein A (SP-A), that plays a critical role in cytoskeleton organization and Golgi budding. We report that the recruitment of CD245 strongly enhanced NK cell cytotoxicity. Further, we show that the enhancement of the NK lymphocytes killing ability toward CD137-ligand expressing target cells could result from the induction of CD137 expression following CD245 engagement. The SP-A receptor could therefore represent a novel and promising target in cancer immunotherapy.

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Fc-dependent expression of CD137 on human NK cells: insights into “agonistic” effects of anti-CD137 monoclonal antibodies

Cited by 109 publications

References 29 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

Augmenting Trastuzumab Therapy Against Breast Cancer Through Selective Activation of NK Cells

Identification of CD245 as myosin 18A, a receptor for surfactant A: A novel pathway for activating human NK lymphocytes

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