FcγRIIIb restricts antibody-dependent destruction of cancer cells by human neutrophils

Autor: Louise W. Treffers, Michel van Houdt, Christine W. Bruggeman, Marieke H. Heineke, Xi Wen Zhao, Joris van der Heijden, Sietse Q. Nagelkerke, Paul J. J. H. Verkuijlen, Judy Geissler, Suzanne Lissenberg-Thunnissen, Thomas Valerius, Matthias Peipp, Katka Franke, Robin van Bruggen, Taco W. Kuijpers, Marjolein van Egmond, Gestur Vidarsson, Hanke L. Matlung, Timo K. van den Berg
Přispěvatelé: Molecular cell biology and Immunology, AII - Cancer immunology, CCA - Cancer biology and immunology, APH - Aging & Later Life, Surgery, AGEM - Re-generation and cancer of the digestive system, AGEM - Digestive immunity, Graduate School, General Paediatrics, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, General Internal Medicine, ARD - Amsterdam Reproduction and Development
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Treffers, L W, van Houdt, M, Bruggeman, C W, Heineke, M H, Zhao, X W, van der Heijden, J, Nagelkerke, S Q, Verkuijlen, P J J H, Geissler, J, Lissenberg-Thunnissen, S, Valerius, T, Peipp, M, Franke, K, van Bruggen, R, Kuijpers, T W, van Egmond, M, Vidarsson, G, Matlung, H L & van den Berg, T K 2019, ' FcγRIIIb restricts antibody-dependent destruction of cancer cells by human neutrophils ', Frontiers in Immunology, vol. 10, no. JAN, 03124 . https://doi.org/10.3389/fimmu.2018.03124
Frontiers in Immunology, Vol 9 (2019)
Frontiers in Immunology, 10(JAN):03124
Frontiers in immunology, 9:3124. Frontiers Media S.A.
Frontiers in Immunology
ISSN: 1664-3224
DOI: 10.3389/fimmu.2018.03124
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: