title: Analysis of the Effects of the Bruton's tyrosine kinase (Btk) Inhibitor Ibrutinib on Monocyte Fcγ Receptor (FcγR) Function.
abstract: The irreversible Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown efficacy against B-cell tumors such as chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Fcγ receptors (FcγR) on immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses, but many such responses involve Btk. Here we tested the effects of ibrutinib on FcγR-mediated activities in monocytes. We found that ibrutinib did not affect monocyte FcγR-mediated phagocytosis, even at concentrations higher than those achieved physiologically, but suppressed FcγR-mediated cytokine production. We confirmed these findings in macrophages from Xid mice in which Btk signaling is defective. Because calcium flux is a major event downstream of Btk, we tested whether it was involved in phagocytosis. The results showed that blocking intracellular calcium flux decreased FcγR-mediated cytokine production but not phagocytosis. To verify this, we measured activation of the GTPase Rac, which is responsible for actin polymerization. Results showed that ibrutinib did not inhibit Rac activation, nor did the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester). We next asked whether the effect of ibrutinib on monocyte FcγR-mediated cytokine production could be rescued by IFNγ priming because NK cells produce IFNγ in response to antibody therapy. Pretreatment of monocytes with IFNγ abrogated the effects of ibrutinib on FcγR-mediated cytokine production, suggesting that IFNγ priming could overcome this Btk inhibition. Furthermore, in monocyte-natural killer cell co-cultures, ibrutinib did not inhibit FcγR-mediated cytokine production despite doing so in single cultures. These results suggest that combining ibrutinib with monoclonal antibody therapy could enhance chronic lymphocytic leukemia cell killing without affecting macrophage effector function.
authors.affiliation: From the Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130000, China and.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Amanda
authors.initials: A
authors.lastname: Campbell
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Fang
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Shalini
authors.initials: S
authors.lastname: Gautam
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Saranya
authors.initials: S
authors.lastname: Elavazhagan
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Kavin
authors.initials: K
authors.lastname: Fatehchand
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Payal
authors.initials: P
authors.lastname: Mehta
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stiff
authors.affiliation: the Department of Internal Medicine and.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Reader
authors.affiliation: Center for Biostatistics, Ohio State University, Columbus, Ohio 43210.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: the Department of Internal Medicine and.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: the Department of Internal Medicine and.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
authors.affiliation: the Department of Internal Medicine and butchar.2@osu.edu.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Butchar
authors.affiliation: the Department of Internal Medicine and tridandapani.2@osu.edu.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D017452:Receptors, IgG; C551803:ibrutinib; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine
keywords: Btk; Fcγ receptor; cancer therapy; ibrutinib; immunotherapy; interferon; monocyte; signal transduction