FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils

被引：86

作者：

Treffers, Louise W. ^{[1
,2
]}

van Houdt, Michel ^{[1
,2
]}

Bruggeman, Christine W. ^{[1
,2
]}

Heineke, Marieke H. ^{[3
]}

Zhao, Xi Wen ^{[1
,2
]}

van der Heijden, Joris, I ^{[1
,2
]}

Nagelkerke, Sietse Q. ^{[1
,2
,4
]}

Verkuijlen, Paul J. J. H. ^{[1
,2
]}

Geissler, Judy ^{[1
,2
]}

Lissenberg-Thunnissen, Suzanne ^{[1
,2
]}

Valerius, Thomas ^{[5
]}

Peipp, Matthias ^{[5
]}

Franke, Katka ^{[1
,2
]}

van Bruggen, Robin ^{[1
,2
]}

Kuijpers, Taco W. ^{[1
,2
,4
]}

van Egmond, Marjolein ^{[3
]}

Vidarsson, Gestur ^{[1
,2
]}

Matlung, Hanke L. ^{[1
,2
]}

van den Berg, Limo K. ^{[1
,2
,3
]}

机构：

[1] Univ Amsterdam, Amsterdam UMC, Sanquin Res, Amsterdam, Netherlands

[2] Univ Amsterdam, Amsterdam UMC, Landsteiner Lab, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam, Amsterdam Infect & Immun Inst, Amsterdam UMC, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands

[4] Univ Amsterdam, Amsterdam UMC, Ernma Childrens Hosp, Amsterdam, Netherlands

[5] Univ Kiel, Dept Internal Med 2, Div Stem Cell Transplantat & Immunotherapy, Kiel, Germany

来源：

FRONTIERS IN IMMUNOLOGY | 2019年 / 9卷

关键词：

Fc gamma RIIIb; neutrophil; ADCC; cancer; granulocyte; Fc-receptor; CNV; glycoengineering; COPY NUMBER VARIATION; LOW-FUCOSE IGG1; CELLULAR CYTOTOXICITY; PROMOTE PHAGOCYTOSIS; CD20; ANTIBODY; RECEPTOR-III; AFFINITY; BINDING; CD16B; FUCOSYLATION;

D O I：

10.3389/fimmu.2018.03124

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The function of the low-affinity IgG-receptor Fc gamma RIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fc gamma receptors (Fc gamma R), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, Fc gamma RIIIb can cooperate with other Fc gamma R to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of Fc gamma RIIIb during antibody-dependent cellular cytotoxicity (ADCC) by neutrophils toward solid cancer cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting Fc gamma RIIIb using CD16-F(ab')(2) blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on Fc gamma RIIa (CD32a) and the enhanced ADCC seen after Fc gamma RIIIb blockade therefore suggested that Fc gamma RIIIb was competing with Fc gamma RIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil Fc gamma RIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface Fc gamma RIIIb 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 Fc gamma RIIIa (CD16a)-dependent natural killer (NK) cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG(1) heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm Fc gamma RIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.

引用

页数：13

共 72 条

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