PD-1/PD-L1 inhibitor ameliorates silica-induced pulmonary fibrosis by maintaining systemic immune homeostasis

Zhao, Youliang; Hao, Changfu; Li, Meng; Qu, Yaqian; Guo, Yonghua; Deng, Xuedan; Si, Huifang; Yao, Wu

doi:10.1016/j.biopha.2022.112768

Cited by 24 publications

(15 citation statements)

References 26 publications

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“…IL17, which can be induced by IL1, has been described to play a key role in causing pulmonary inflammation and fibrosis in both mice 29, 30 and humans 31 . Interestingly, we also observed conserved induction of the IPA Pathway PD-1 / PD-L1 signaling (in cancer), which has previously been reported to play a role in the promotion of lung fibrosis 32, 33 . Transcription factor regulon activity analysis using SCENIC 34 identified fibrosis-specific regulons, including STAT1, IRF1, IRF7, and CEBPB, that were opposed to the non-fibrotic regulons, which included KDM5A, IF8, and ZBTB7A ( Supp.…”

Section: Resultssupporting

confidence: 74%

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Lang

Gote-Schniering

Porras-Gonzalez

et al. 2023

Preprint

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Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupledex vivocytokine and drug perturbations of human precision-cut lung slices (hPCLS) with scRNAseq and induced a multi-lineage circuit of fibrogenic cell states in hPCLS, which we show to be highly similar to thein vivocell circuit in a multi-cohort lung cell atlas from pulmonary fibrosis patients. Using micro-CT staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in theex vivohPCLS model provides evidence that the basaloid cell state was derived from alveolar type-2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in the hPCLS model and anti-fibrotic drug treatments showed highly cell type specific effects. Our work provides an experimental framework for perturbational single cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration and pathology. We further demonstrate that hPCLS offers novel avenues for scalable, high-resolution drug testing to accelerate anti-fibrotic drug development and translation.

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Section: Resultssupporting

confidence: 74%

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Lang

Gote-Schniering

Porras-Gonzalez

et al. 2023

Preprint

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“…In the study of tumours and viruses, it has been found that high concentrations of antigens for a long time can induce CD4 + T cells to express PD-1, decreases the IFN-γ expression of lymphocytes and lead to immune exhaustion [ 16 , 17 ]. Some studies also found that silica instillation significantly elevated the expression of immune checkpoint molecules such as PD-1 in mice and suggested that silica is an important risk factor for T-cellcell exhaustion [ 18 , 19 ]. Due to the negative correlation between PD-1 and IFN-γ and there is no study on T cell exhaustion in silicosis patients before, this study analysed the expression of PD-1 in silicosis and found that the peripheral blood lymphocytes of patients with silicosis highly expressed PD-1, and the PD-1 highly expression can inhibited the secretion of IFN-γ by lymphocytes (especially CD4 + T cells).…”

Section: Discussionmentioning

confidence: 99%

The exhaustion of lymphocytes is the main factor that decreases the sensitivity of QFT-GIT detection in silicosis

Huang

et al. 2022

BMC Immunol

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Background Tuberculosis infection is a major complication of silicosis, but there is no study on whether silicosis can affect the sensitivity of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. This study will analyze the relationship between silicosis and QFT-GIT, determine the main factor of the QFT-GIT sensitivity decrease in silicosis and explore the methods to increase the sensitivity. Methods Silicosis patients with positive tubercle bacillus cultures were collected. The QFT-GIT, flow cytometry and blocking antibodies were used. Results The sensitivity of QFT-GIT in silicosis patients (58.46%) was significantly decreased and the expression of PD-1 on T cells and CD56+NK cells in pulmonary tuberculosis combined with silicosis were higher than normal tuberculosis patients and silicosis only patients. Further analysis found that the ratio of PD-1+CD4+T and IFN-γwere negatively correlated and blockaded the PD-1 pathway with antibodies can restore the sensitivity of QFT-GIT in silicosis. Conclusions This is the first study to analyze the relationship between immune exhaustion and QFT-GIT in silicosis and found that the sensitivity of QFT-GIT was decreased by the expression of PD-1 on lymphocytes. Antibody blocking experiments increased the expression of IFN-γ and provided a new method to improve the sensitivity of QFT in silicosis. The study also found that silicosis can increase PD-1 expression. As PD-1 functions in infectious diseases, it will promote immune exhaustion in silicosis and lead to tuberculosis from latent to active infection. The study provided theoretical evidence for the diagnosis and immunotherapy of silicosis complications, and it has great value in clinical diagnostics and treatment.

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“…Studies in individuals with IPF and mouse models suggest that the PD-1/PD-L1 axis has a more predominant profibrotic role than its immunomodulatory role in IPF. Thus, numerous preclinical studies were conducted to investigate the feasibility of treating IPF by targeting the PD-1/PD-L1 axis in mice models ( 20 , 21 , 25 , 26 , 28 , 29 ). The majority of studies identified that blockade of the PD-1/PD-L1 axis using PD-L1 mAb could attenuate the severity of pulmonary fibrosis in mice models.…”

Section: Is It Rational To Target the Pd-1/pd-l1 Axis For Ipf Treatment?mentioning

confidence: 99%

“…Consistent with the PD-L1 expression level in the lung tissue of the bleomycin-driven pulmonary fibrosis murine model, Cui and colleagues observed that PD-L1 was also positively expressed in the lung of IL-6 knockout mice ( 20 ). In a silica-induced pulmonary fibrosis mice model, the researchers adopted multiple assays to evaluate the changes in the mRNA and protein expression levels of PD-1 and PD-L1 in the lung ( 28 ). They demonstrated that silica exposure resulted in altered proportions and subtypes of T and B cells in immune organs, as well as the abnormalities of PD-1, PD-L1, and CTLA-4 expressions on these cells, leading to an imbalanced systemic immune homeostasis.…”

Section: Pd-1/pd-l1 Axis and Ipf In Animal Modelsmentioning

confidence: 99%

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

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PD-1/PD-L1 inhibitor ameliorates silica-induced pulmonary fibrosis by maintaining systemic immune homeostasis

Cited by 24 publications

References 26 publications

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Ex vivotissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

The exhaustion of lymphocytes is the main factor that decreases the sensitivity of QFT-GIT detection in silicosis

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

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