Ivacaftor decreases monocyte sensitivity to interferon-γ in people with cystic fibrosis

Abstract

Management of cystic fibrosis has been revolutionised by the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. These compounds treat the underlying molecular basis of the disease by increasing activity of defective CFTR channels, which improves many clinical parameters and enhances patient quality of life [1]. Next-generation modulators, also known as triple combination therapy, promise to be highly efficacious in up to 90% of patients [2] and will likely dramatically change the landscape of cystic fibrosis disease. Studies examining individuals before and after initiation of CFTR modulators have revealed novel functions of CFTR and shown that CFTR modulators do not reverse all disease manifestations [3-5]. Thus, knowledge of the post-modulator cystic fibrosis disease state is crucial for understanding what continued therapies will be needed for people with cystic fibrosis and what new challenges may arise. In prior work, we sought to identify immune pathways that were differentially modulated in the presence and absence of CFTR activity [6]. We isolated monocytes from subjects with G551D-CFTR mutations before and after initiation of the modulator ivacaftor. Using an unbiased proteomics approach, we identified post-ivacaftor changes in the monocyte plasma membrane proteome consistent with decreased interferon (IFN)-γ-related responses. Although both monocytes and macrophages from individuals with cystic fibrosis have been shown to manifest abnormal immune responses, myeloid IFN-γ responses had not previously been reported as altered in people with cystic fibrosis [7]. In the current study, we took advantage of a second cohort of subjects with cystic fibrosis who were initiating ivacaftor to test the hypothesis that ivacaftor dampens monocyte sensitivity to IFN-γ.

Ivacaftor modifies cystic fibrosis neutrophil phenotype in subjects with R117H residual function CFTR mutations

“…Sweat chloride changed from 77.5 (+/-4) mmol/l to 52.1 (+/-5.61) after 7 days of treatment (p<0.001, paired t-test) confirming a pharmacodynamic response to therapy, FEV 1 also improved at 7 days as detailed in a contemporaneous study in the same patient cohort (10).…”

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis

“…ATF3 (Activating Transcription Factor 3, FDR = 3.11 × 10 −10 ) binds CRE elements in DNA and represses transcription, and has been shown to negatively regulate pro-inflammatory cytokine expression in macrophages ( Rosenberger et al., 2008 ; Labzin et al., 2015 ). We recently showed that monocytes from the same cohort described here exhibit a decrease in ex vivo responsiveness to IFNγ after subjects have received ivacaftor for 7 days ( Hisert et al., 2020 ). An increased expression of genes that deactivate or dampen inflammatory signaling could partly explain why transcriptome data predicted that these monocytes have a more inflammatory phenotype while the same cells, when stimulated ex vivo , exhibited decreased IFNγ responses.…”

“…In order to characterize the inflammatory phenotype of in vivo blood monocytes in people with CF, and to determine how cellular phenotypes change in response to CFTR modulator therapy, we have used unbiased “omics” methods to identify changes in freshly isolated peripheral blood monocytes following initiation of ivacaftor in people with susceptible CFTR mutations. Previously we identified changes in the monocyte plasma-membrane associated proteome in subjects with CFTR-G551D mutations that suggested that CFTR modulator therapy causes a decrease in monocyte IFN γ responses ( Hisert et al., 2016 ), a hypothesis that we have since confirmed ( Hisert et al., 2020 ). Here we describe how restoration of CFTR activity by ivacaftor acutely changes the peripheral blood monocyte transcriptome and plasma chemokines in a cohort of adults with CF and the CFTR mutation R117H.…”

“…Five subject had recent clinical sputum cultures positive for Staphylococcus aureus ( ± Haemophilus , Pseudomonas or Acinetobacter species), two subjects had recent Pseudomonas aeruginosa positive sputum cultures, three subjects had a history of P. aeruginosa positive sputum cultures, and one subject had not recently produced sputum. All subjects experienced a pronounced decrease in sweat chloride, and the cohort also experienced a statistically significant increase in FEV 1, within 48 h of ivacaftor treatment, and both changes were maintained at day 7 ( Hisert et al., 2020 ).…”

Airway Inflammation and Host Responses in the Era of CFTR Modulators

“…The effects of CFTR modulators on inflammation in general, and the impact they have on intrinsic defects of the innate immune response in PWCF, are thus far under-characterised. The effects of CFTR modulators in clinical trials have focused on pulmonary function, PEx, and quality of life measures, which are important clinical outcomes [ 6 , 7 , 8 , 9 , 10 , 11 ] and are also required for regulatory approval [ 116 ]. Furthermore, existing published research is mainly limited to the effects of the potentiator, ivacaftor (IVA), with little data relating to the other modulator therapies available as yet.…”