Author:
Jatin Vyas (US)
Abstract:
Inhibition of Bruton’s tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is the preferred treatment for chronic B-lymphocyte leukemia and mantle cell lymphoma. However, IBT-treated patients are highly susceptible to invasive fungal infections, including invasive aspergillosis, though the mechanism is poorly understood. Neutrophils are the primary line of defense against invasive fungal infections; therefore, we examined the impact of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNFα fully compensated for these IBT-associated defects. TNFα also restored the effector activity of neutrophils treated with acalabrutinib and zanubrutinib, newer generation BTK inhibitors. Blocking TNFα with infliximab did not impact ROS production in healthy neutrophils but prevented exogenous TNFα from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNFα was independent of transcription, as ROS production was rescued even after using a transcription inhibitor on IBT-treated neutrophils. Moreover, the addition of TNFα immediately rescued ROS production in IBT-treated neutrophils indicating that TNFα worked through a BTK-independent signaling pathway. Finally, TNFα restored the effector activity of primary neutrophils from patients on IBT therapy, recapitulating our in vitro findings. Altogether, our data indicate that TNFα rescues the block in antifungal immunity imposed by the inhibition of BTK in primary human neutrophils.
Abstract Number: 61
Conference Year: 2024
Conference abstracts, posters & presentations
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Title
Author
Year
Number
Poster
-
v
Tianyu Lianga, Nir Osherovb, Ruoyu Lia, Qiqi Wanga, Wei Chena, Zhe Wana, Wei Liua*
2024
n/a
-
v
Jillian Simard, MD,1 Christopher Melani, MD,2
Rahul Lakhotia, MD,1
Michail S. Lionakis, MD
ScD,*,3
Stefania Pittaluga, MD PhD,4
James D. Phelan, PhD,*,1 Jagan R. Muppidi, MD
PhD,*,1
Lydia L. Chou, CRNP,*,1
Matthias Holdhoff, MD PhD,*,5 Michael Glantz, MD PhD,*,6
John A. Butman, MD PhD,*,7 Andrea Nicole Lucas, RN,*,8
Seth M. Steinberg, PhD,*,9
Elaine
S. Jaffe, MD,4
Louis M. Staudt, MD PhD,1
Wyndham H. Wilson, MD PhD,1 Mark Roschewski, MD102020
n/a
-
v
Mark Roschewski, MD,1
Christopher Melani, MD,2
Rahul Lakhotia, MD,3
Stefania Pittaluga, MD
PhD,4
James D. Phelan, PhD,*,3
Cody Peer, PhD,*,5 Michail S. Lionakis, MD ScD,*,6 Lydia
L. Chou, CRNP,*,3 Matthias Holdhoff, MD PhD,*,7 Michael Glantz, MD PhD,*,8 Jan Drappatz, MD,*,9
Catherine Lai, MD MPH,10 John A. Butman, MD PhD,*,11 Andrea Nicole Lucas, RN,*,12 Seth
M. Steinberg, PhD,*,13 William D. Figg, PhD,*,14 Elaine S. Jaffe, MD,4
S. Percy Ivy, MD,*,15
Richard F. Little, MDMPH,16 Louis M. Staudt, MD PhD,3
Wyndham H. Wilson, MD PhD32020
n/a
-
v
Binav Baral, MD,*,1 Prasanth Lingamaneni,*,2 Trilok Shrivastava, MD,*,3 Maryam Zia,4 Ishaan Vohra, MD,*,2
Krishna Rekha Moturi*,32020
903
n/a
-
v
Maxwell Green1, Scout Treadwell1, Geetha Gowda1, John Carlson, MD, PhD2
2023
610
n/a
-
v
Catherine Blackwood, PhD1 , Angela Lemons, MS2 , Rachael Rush3 , Walter McKinney2 , Dori Germolec4 , Donald Beezhold, PhD2 , Brett Green, PhD5 , Tara Croston, PhD6
2023
583
n/a
-
v
Catherine Blackwood, PhD1 , Angela Lemons, MS2 , Rachael Rush3 , Walter McKinney2 , Dori Germolec4 , Donald Beezhold, PhD2 , Brett Green, PhD5 , Tara Croston, PhD6
2023
583
n/a
-
v
Jennifer Roper, MD1, Sebastian Ochoa, MD2, Anahita
Agharahimi, MSN, CRNP2, Justina Pfister, RN2, Magdalena
Walkiewicz, PhD2, Amanda Urban, DNP, CRNP3, Rajarshi
Ghosh, PhD2, Michail Lionakis, MD, ScD2, Lisa Kohn, MD, PhD4, Kenneth Olivier, MD, MPH2, Alexandra Freeman, MD22023
516
n/a
-
v
Utkucan Acar, Gloria Sheng, Terrie Ahn, Lisa Kohn, Maria Garcia Lloret, Manish Butte
2022
82
n/a
-
v
C Gutierrez Perez1*, S Dhingra1,2, SM Kwansy3, TJ Opperman3, RA Cramer1
2022
93