BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by exogenous TNFα

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

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