Original Research ARTICLE
FcγRIIIb restricts antibody-dependent destruction of cancer cells by human neutrophils
- 1AMC-Sanquin Landsteiner Laboratory, Netherlands
- 2Department of Molecular Cell Biology and Immunology, VU University Medical Center, Netherlands
- 3Sektion für Stammzell und Immuntherapie, Klinik für Innere Medizin II Hämatologie und Onkologie, Universitätsklinikum Schleswig-Holstein, Germany
- 4Emma Children's Hospital, Amsterdam University Medical Center, Netherlands
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 towards 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 towards tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.
Keywords: FcγRIIIb, Neutrophil (PMN), ADCC (antibody-dependent cellular cytotoxicity), Cancer, granulocyte, Fc-receptor, CNV, Glycoengineering
Received: 07 Oct 2018;
Accepted: 18 Dec 2018.
Edited by:Alexandre Corthay, Department of Pathology, Oslo University Hospital, Norway
Reviewed by:Alessandro Poggi, Dipartimento delle Terapie Oncologiche Integrate, Ospedale Policlinico San Martino, Italy
Kia Joo Puan, Singapore Immunology Network (A*STAR), Singapore
Dhiraj Kumar, University of Texas MD Anderson Cancer Center, United States
Copyright: © 2018 Treffers, van Houdt, Bruggeman, Heineke, Zhao, van der Heijden, Nagelkerke, Verkuijlen, Geissler, Lissenberg-Thunnissen, Valerius, Peipp, Franke, van Bruggen, Kuijpers, van Egmond, Vidarsson, Matlung and van den Berg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Ms. Louise W. Treffers, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands, firstname.lastname@example.org
Dr. Hanke L. Matlung, AMC-Sanquin Landsteiner Laboratory, Amsterdam, Netherlands, H.Matlung@sanquin.nl