Fc?RIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils.

ABSTRACT: The function of the low-affinity IgG-receptor Fc?RIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fc? receptors (Fc?R), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, Fc?RIIIb can cooperate with other Fc?R to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of Fc?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?RIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on Fc?RIIa (CD32a) and the enhanced ADCC seen after Fc?RIIIb blockade therefore suggested that Fc?RIIIb was competing with Fc?RIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil Fc?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?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?RIIIa (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 Fc?RIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.

SUBMITTER: Treffers LW 

PROVIDER: S-EPMC6363688 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature