Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy

Abstract

IntroductionCystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF.MethodsPeripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry.ResultsElexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (–50.2%, p<0.001).ConclusionTreatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

Plasma levels of chemokines decrease during elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis

“…Our findings indicate that not only IL-8, but also three other CXC chemokines are downregulated in response to ETI, suggesting mainly a decline of neutrophilic inflammation. Overall, these results are in line with previous studies reporting a normalisation of circulating neutrophil counts [ 9 ], reduced neutrophil-associated systemic cytokines [ 12 , 13 ] and reduced inflammatory airway markers such as neutrophil elastase in pwCF receiving ETI [ 14 , 15 ].…”

“…Data from previous studies analysing the effects of mono and dual combination CFTR modulators on inflammatory markers in sputum and plasma from pwCF are inconsistent [ [5] , [6] , [7] , [8] ]. Recent studies have reported a normalisation of circulating neutrophil counts [ 9 ], improvements in monocyte/macrophage function [ 10 , 11 ], and reduction in airway and systemic proinflammatory cytokines [ [12] , [13] , [14] , [15] , [16] ] in pwCF receiving triple combination ETI. Overall, data on the immunological impact of CFTR modulator therapy are scarce and incomplete.…”

Regulatory T cells in lung disease and transplantation

“…The hallmark of CF is chronic unremitting lung disease, a major cause of morbidity and mortality in CF patients. This condition is characterized by chronic infections, immune dysfunction, and dysregulated airway inflammatory responses, evidenced by decreased Treg cell activity and excessive inflammatory reactions [ 186 , 187 ]. Treg cells, especially CD4 + CD25 + Treg cells, play a crucial role in maintaining the balance between anti-inflammatory and pro-inflammatory mediators, thereby stabilizing the immune system [ 187 , 188 ].…”

“…Furthermore, highly effective CFTR modulators have been developed to improve the quality of life for patients with multiple CFTR mutations. Treatment with Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to down-regulate blood levels of pro-inflammatory factors IL-6, IL-8 and IL-17A and up-regulate the percentages of Treg cells in CF patients [ 186 ]. ELX/TEZ/IVA, the first approved triple CFTR modulator therapy, effectively addresses inflammation and immune dysregulation caused by CFTR deficiency [ 194 ].…”

“…Due to their immunomodulatory and anti-inflammatory characteristics, Treg cells play a pivotal role in managing lung diseases. Augmenting Treg cell numbers or enhancing their function can effectively inhibit inflammation and slow down the progression of conditions such as autoimmune lung diseases, asthma, ARDS, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, etc [ 170 , 182 , 186 , 237 , 302–304 ]. Conversely, for certain lung diseases like lung cancer, restraining the proliferation and differentiation of Treg cells is essential to reduce tumour burden and increase anti-tumor immune response, thus achieving therapeutic outcomes [ 220 , 305 , 306 ].…”