Researchers Find Cancer-Linked Protein to Drive Fatal Lung Disease

Recent research from Cedars-Sinai shows that a protein associated with cancer growth may play a role in developing idiopathic pulmonary fibrosis, a fatal lung disease. This discovery was made in a laboratory involving human tissue samples and mice, and indicates that existing anti-cancer treatments inhibiting the PD-L1 protein are potential candidates for treating the disease.

The research team focused on fibroblast cells in this study, which create proteins to build the extracellular matrix that offers biochemical support in tissues. In idiopathic pulmonary fibrosis, these cells are defective and create deposits of fibrous scar tissues in normal lung tissue in an invasive manner. This accumulation of scar tissue causes functional impairment in the lung resulting in shortness of breath, shallow breathing, aching in muscles and joints, and several other symptoms.

By analyzing lung tissue samples from patients with idiopathic pulmonary fibrosis, the researchers discovered that these invasive fibroblasts were secreting excessively high levels of PD-L1, a protein on normal cells that prevents autoimmune attack. By expressing elevated levels of these proteins, the invasive fibroblasts appear to avoid normal degradation by the immune system.

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In the experiment with mice, the researchers administered mice with either an injection of defective fibroblast cells, or healthy cells. The team found that those injected with the defective cells developed signs of idiopathic pulmonary fibrosis, whereas those administered healthy cells did not. They also found that the severity of the disease was reduced using genetic and antibody techniques aimed to inhibit PD-L1.

“Cumulatively, these results identify PD-L1 as a driver of fibroblast invasion in idiopathic pulmonary fibrosis and support PD-L1 as a potential therapeutic target for the condition,” said Dianhua Jiang, MD, PhD, professor of Medicine at Cedars-Sinai. Alongside Jiang was co-author Paul Noble, MD, professor of Medicine and chair of the Department of Medicine, director of the Women’s Guild Lung Institute and the Vera and Paul Guerin Family Distinguished Chair in Pulmonary Medicine at Cedars-Sinai. Their work was published in the journal JCI Insight.

The team is currently designing a proposition for a Phase I clinical trial using PD-L1-inhibitors to treat the disease. If the drug is deemed to be safe for human use, it would then be further tested in trials to evaluate the efficacy of its use.

The current PD-L1-inhibitors approved by the FDA are intended for use in cancer treatment. With many cancer cells evading immune response by similar PD-L1 masking mechanisms, these cancer treatments would logically be effective in preventing invasive fibroblasts from invading cells.

“Our proposal is to use one of these FDA-approved drugs in a clinical trial for idiopathic pulmonary fibrosis,” stated Noble.

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Idiopathic pulmonary fibrosis is a chronic disease with an unknown cause, affecting over 100,000 U.S. citizens. Excessive fibrosis, or accumulation of scar tissue, caused by the disease can eventually damage the lungs to the point where oxygen transport is extremely difficult. The disease typically becomes fatal, with most patients dying within five years of diagnosis.

“At present, there is no known cure for this devastating condition,” said Paul Noble, MD, professor of Medicine and chair of the Department of Medicine, director of the Women’s Guild Lung Institute and the Vera and Paul Guerin Family Distinguished Chair in Pulmonary Medicine at Cedars-Sinai. “Current FDA- approved drugs only slow the fibrosis in certain individuals or treat some symptoms. This study opens a pathway for developing a treatment for idiopathic pulmonary fibrosis.”

READ MORE: Biomarkers in idiopathic pulmonary fibrosis

Sources: JCI Insight, Cedars-Sinai