The Experts below are selected from a list of 8712 Experts worldwide ranked by ideXlab platform
Georg Kraal - One of the best experts on this subject based on the ideXlab platform.
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cd47 signal regulatory protein α sirpα interactions form a barrier for antibody mediated Tumor Cell Destruction
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Xi Wen Zhao, Ellen M Van Beek, Karin Schornagel, Hans Van Der Maaden, Michel Van Houdt, Marielle A Otten, Pascal Finetti, Marjolein Van Egmond, Takashi Matozaki, Georg KraalAbstract:Monoclonal antibodies are among the most promising therapeutic agents for treating cancer. Therapeutic cancer antibodies bind to Tumor Cells, turning them into targets for immune-mediated Destruction. We show here that this antibody-mediated killing of Tumor Cells is limited by a mechanism involving the interaction between Tumor Cell-expressed CD47 and the inhibitory receptor signal regulatory protein-α (SIRPα) on myeloid Cells. Mice that lack the SIRPα cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma Cells in vivo. Moreover, interference with CD47–SIRPα interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRPα significantly enhances the in vitro killing of trastuzumab-opsonized Her2/Neu-positive breast cancer Cells by phagocytes. Finally, the response to trastuzumab therapy in breast cancer patients appears correlated to cancer Cell CD47 expression. These findings demonstrate that CD47–SIRPα interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of Tumor Cells. This provides a rational basis for targeting CD47–SIRPα interactions, using for instance the antagonistic antibodies against human SIRPα described herein, to potentiate the clinical effects of cancer therapeutic antibodies.
Huntaeg Chung - One of the best experts on this subject based on the ideXlab platform.
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fibronectin activates murine peritoneal macrophages for Tumor Cell Destruction in the presence of ifn gamma
Biochemical and Biophysical Research Communications, 1995Co-Authors: Changduk Jun, Hyunju Yoon, Hyungmin Kim, Huntaeg ChungAbstract:Increasing evidence indicates that interaction of Cells with fibronectin (Fn) affects many aspects of Cellular responses including growth, morphology, differentiation, and activation. However, it is not known whether Fn could activate macrophages for the Tumor Cell killing. Here we report that Fn provides a signal for murine macrophage activation to Tumoricidal activity. Tumoricidal activity was determined by the release of 51Cr from prelabeled P815 mastocytoma target Cells. Fn alone had no effect, whereas recombinant interferon-gamma (rIFN-gamma) weakly induced C57BL/6 murine macrophages to kill P815 mastocytoma Cells. However, combination of Fn with rIFN-gamma synergized to activate macrophages to lyse Tumor Cells in a dose dependent manner. Secretion of nitric oxide (NO) correlated with Tumor Cell killing, and the activated macrophages failed to kill Tumor Cell targets in the presence of NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of NO synthase (NOS). Fn, unlike lipopolysaccharide (LPS), alone had no effect on NO synthesis by itself and did not induce bioactive Tumor necrosis factor-alpha (TNF-alpha) secretion from murine peritoneal macrophages. The data illustrate the potential for Fn to activate macrophage-mediated antiTumor mechanisms in addition to its better characterized role as a Cell adhesion molecule.
Alexander L Rakhmilevich - One of the best experts on this subject based on the ideXlab platform.
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cd40 ligation activates murine macrophages via an ifn γ dependent mechanism resulting in Tumor Cell Destruction in vitro
Journal of Immunology, 2005Co-Authors: Ilia N Buhtoiarov, Hillary D Lum, Gideon Berke, Donna M Paulnock, Paul M Sondel, Alexander L RakhmilevichAbstract:We have shown previously that agonistic anti-CD40 mAb induced T Cell-independent antiTumor effects in vivo. In this study, we investigated mechanisms of macrophage activation with anti-CD40 mAb treatment, assessed by the antiTumor action of macrophages in vitro. Intraperitoneal injection of anti-CD40 mAb into C57BL/6 mice resulted in activation of peritoneal macrophages capable of suppressing B16 melanoma Cell proliferation in vitro, an effect that was greatly enhanced by LPS and observed against several murine and human Tumor Cell lines. Anti-CD40 mAb also primed macrophages in vitro to mediate cytostatic effects in the presence of LPS. The Tumoristatic effect of CD40 ligation-activated macrophages was associated with apoptosis and killing of Tumor Cells. Activation of macrophages by anti-CD40 mAb required endogenous IFN-gamma because priming of macrophages by anti-CD40 mAb was abrogated in the presence of anti-IFN-gamma mAb, as well as in IFN-gamma-knockout mice. Macrophages obtained either from C57BL/6 mice depleted of T and NK Cells by Ab treatment, or from scid/beige mice, were still activated by anti-CD40 mAb to mediate cytostatic activity. These results argued against the role of NK and T Cells as the sole source of exogenous IFN-gamma for macrophage activation and suggested that anti-CD40 mAb-activated macrophages could produce IFN-gamma. We confirmed this hypothesis by detecting intracytoplasmic IFN-gamma in macrophages activated with anti-CD40 mAb in vivo or in vitro. IFN-gamma production by macrophages was dependent on IL-12. Taken together, the results show that murine macrophages are activated directly by anti-CD40 mAb to secrete IFN-gamma and mediate Tumor Cell Destruction.
Xi Wen Zhao - One of the best experts on this subject based on the ideXlab platform.
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FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils
Frontiers Media S.A., 2019Co-Authors: Louise W. Treffers, Xi Wen Zhao, Michel Van Houdt, Christine W. Bruggeman, Marieke H. Heineke, Joris Van Der Heijden, Sietse Q. Nagelkerke, Paul J. J. H. Verkuijlen, Judy GeisslerAbstract:The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intraCellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent Cellular cytotoxicity (ADCC) by neutrophils toward solid cancer Cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target Cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface FcγRIIIb expression. Individuals with one copy of FCGR3B showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) Cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG1 heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward Tumor Cells and a potential target for enhancing Tumor Cell Destruction by neutrophils
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Data_Sheet_1_FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils.PDF
2019Co-Authors: Louise W. Treffers, Xi Wen Zhao, Michel Van Houdt, Christine W. Bruggeman, Marieke H. Heineke, Joris Van Der Heijden, Sietse Q. Nagelkerke, Paul J. J. H. Verkuijlen, Judy Geissler, Suzanne Lissenberg-thunnissenAbstract:The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intraCellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent Cellular cytotoxicity (ADCC) by neutrophils toward solid cancer Cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target Cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface FcγRIIIb expression. Individuals with one copy of FCGR3B showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) Cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG1 heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward Tumor Cells and a potential target for enhancing Tumor Cell Destruction by neutrophils.
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cd47 signal regulatory protein α sirpα interactions form a barrier for antibody mediated Tumor Cell Destruction
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Xi Wen Zhao, Ellen M Van Beek, Karin Schornagel, Hans Van Der Maaden, Michel Van Houdt, Marielle A Otten, Pascal Finetti, Marjolein Van Egmond, Takashi Matozaki, Georg KraalAbstract:Monoclonal antibodies are among the most promising therapeutic agents for treating cancer. Therapeutic cancer antibodies bind to Tumor Cells, turning them into targets for immune-mediated Destruction. We show here that this antibody-mediated killing of Tumor Cells is limited by a mechanism involving the interaction between Tumor Cell-expressed CD47 and the inhibitory receptor signal regulatory protein-α (SIRPα) on myeloid Cells. Mice that lack the SIRPα cytoplasmic tail, and hence its inhibitory signaling, display increased antibody-mediated elimination of melanoma Cells in vivo. Moreover, interference with CD47–SIRPα interactions by CD47 knockdown or by antagonistic antibodies against CD47 or SIRPα significantly enhances the in vitro killing of trastuzumab-opsonized Her2/Neu-positive breast cancer Cells by phagocytes. Finally, the response to trastuzumab therapy in breast cancer patients appears correlated to cancer Cell CD47 expression. These findings demonstrate that CD47–SIRPα interactions participate in a homeostatic mechanism that restricts antibody-mediated killing of Tumor Cells. This provides a rational basis for targeting CD47–SIRPα interactions, using for instance the antagonistic antibodies against human SIRPα described herein, to potentiate the clinical effects of cancer therapeutic antibodies.
Changduk Jun - One of the best experts on this subject based on the ideXlab platform.
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fibronectin activates murine peritoneal macrophages for Tumor Cell Destruction in the presence of ifn gamma
Biochemical and Biophysical Research Communications, 1995Co-Authors: Changduk Jun, Hyunju Yoon, Hyungmin Kim, Huntaeg ChungAbstract:Increasing evidence indicates that interaction of Cells with fibronectin (Fn) affects many aspects of Cellular responses including growth, morphology, differentiation, and activation. However, it is not known whether Fn could activate macrophages for the Tumor Cell killing. Here we report that Fn provides a signal for murine macrophage activation to Tumoricidal activity. Tumoricidal activity was determined by the release of 51Cr from prelabeled P815 mastocytoma target Cells. Fn alone had no effect, whereas recombinant interferon-gamma (rIFN-gamma) weakly induced C57BL/6 murine macrophages to kill P815 mastocytoma Cells. However, combination of Fn with rIFN-gamma synergized to activate macrophages to lyse Tumor Cells in a dose dependent manner. Secretion of nitric oxide (NO) correlated with Tumor Cell killing, and the activated macrophages failed to kill Tumor Cell targets in the presence of NG-monomethyl-L-arginine (NGMMA), a competitive inhibitor of NO synthase (NOS). Fn, unlike lipopolysaccharide (LPS), alone had no effect on NO synthesis by itself and did not induce bioactive Tumor necrosis factor-alpha (TNF-alpha) secretion from murine peritoneal macrophages. The data illustrate the potential for Fn to activate macrophage-mediated antiTumor mechanisms in addition to its better characterized role as a Cell adhesion molecule.
