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Bruton’s tyrosine kinase inhibitors impair FcγRIIA-driven platelet responses to bacteria in chronic lymphocytic leukemia

Naylor-Adamson, Leigh; Chacko, Anisha; Booth, Zoe; Caserta, Stefano; Jarvis, Jenna; Khan, Sujoy; Hart, Simon P.; Rivero, Francisco; Allsup, David J.; Arman, Mònica

Authors

Leigh Naylor-Adamson

Anisha Chacko

Zoe Booth

Jenna Jarvis

Sujoy Khan

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Dr David Allsup D.J.Allsup@hull.ac.uk
Senior Lecturer in Haematology and Honorary Consultant

Mònica Arman



Abstract

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton’s tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbβ3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbβ3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.

Citation

Naylor-Adamson, L., Chacko, A., Booth, Z., Caserta, S., Jarvis, J., Khan, S., …Arman, M. (2021). Bruton’s tyrosine kinase inhibitors impair FcγRIIA-driven platelet responses to bacteria in chronic lymphocytic leukemia. Frontiers in immunology, 12, Article 766272. https://doi.org/10.3389/fimmu.2021.766272

Journal Article Type Article
Acceptance Date Oct 26, 2021
Online Publication Date Nov 29, 2021
Publication Date Nov 29, 2021
Deposit Date Nov 29, 2021
Publicly Available Date Dec 2, 2021
Journal Frontiers in Immunology
Electronic ISSN 1664-3224
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 12
Article Number 766272
DOI https://doi.org/10.3389/fimmu.2021.766272
Keywords Platelet; FcγRIIA; Staphylococcus aureus; Escherichia coli; Bruton’s tyrosine kinase inhibitor; Ibrutinib; Acalabrutinib; Chronic lymphocytic leukemia
Public URL https://hull-repository.worktribe.com/output/3866331

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Copyright Statement
Copyright © 2021 Naylor-Adamson, Chacko, Booth, Caserta, Jarvis, Khan, Hart, Rivero, Allsup and Arman. 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.



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