Immunotherapy: A new hope for lung fibrosis?

By Christopher Vaughan

June 3, 2020

Idiopathic lung fibrosis is a debilitating disease with a dismal prognosis and which is currently is incurable. The disease is caused by progressive scarring in the lungs, making it difficult to breathe for patients who become dependent on oxygen to live. Now a team of researchers led by assistant professor of pathology Gerlinde Wernig, MD, at the Stanford Institute for Stem Cell Biology and Regenerative Medicine has shown that scar tissue cells called fibroblasts are able to proliferate by avoiding immune surveillance, and that a cure may lie in reactivating that immune function.  Their work was published online in the journal Nature Communications on June 3, 2020.

Immune surveillance is a mechanism the body uses to keep tissues healthy and to eliminate cells that might cause disease.  For instance, this process is used to detect and remove pre-cancerous cells. More advanced cancer cells can resist this process by presenting molecular signals that dampen protective immunity. 

One of these signalling proteins, CD47, is used by cancer cells as a“don’t eat me” signal that stops immune cells called macrophages from devouring and destroying cells. Another, PD-L1, is sometimes used by aberrent cells to keep macrophages and other immune cells called T-cells from attacking them.

“In idiopathic lung disease, these fibroblasts  behave almost like cancer cells,” Wernig says. “They grow over normal lung structures, obliterating airways and blocking the passage of air in and out of the blood.” And like cancer cells, Wernig has discovered, fibroblasts also evade the immune system using these immune-dampening proteins.

In previous work, Gerlinde Wernig, MD, and her colleagues showed that a gene called JUN is a master regulator of fibrotic processes in mice. Turning on the gene, caused fibrosis of the lung, liver, skin, bone marrow and the kidney in a mouse model. In the current work, Wernig and her colleagues showed that in tissue samples from end-stage lung fibrosis patients, JUN directly activates the genes for CD47 and PD-L1, leading to increased production of these proteins in fibrotic scar-forming lung cells.

The researchers also showed the critical role of another inflammatory molecule called IL-6  in fibrotic disease. “When we looked at clinical tissue samples from lung fibrosis patients, we saw a huge increase in IL-6,” Wernig says. “IL-6 is known to be associated with chronic inflammatory disease, but it wasn’t clear how the molecule was contributing to the scarring process.” The researchers subsequently found that JUN activation also leads to increased IL-6 levels, which in turn amplify the production of CD47, thus further increasing the fibroblasts resistance to immune-cell regulation.

When the researchers blocked signaling  by IL-6 and CD47simultaneously,  the treatment dramatically improved lung tissue by increasing the clearance of fibrotic cells. “In mice, with the combined blockade of inflammation and the “don’t eat me signal” we were able to eliminate established, end-stage fibrosis”, Wernig says.

“This study presents hope for a new treatment option that could improve the condition of patients with lung fibrosis,” Wernig said. 

Other Stanford scientists involved in the research were professor of pathology Garry Nolan, PhD; postdoctoral fellows Lu Cui, PhD; Tristan Lerbs, MD;  and former postdoctoral fellows Shih-Yu Chen, PhD and Paola Betancur, PhD; former graduate student Sydney Gordon, PhD; and software developer Jin-Wook Lee, MS. 

The research was supported by the National Heart, Lung and Blood Institute (NHLBI grant 1222520-100-PAPGN, a basic science research grant by Boehringer-Ingelheim, and funding from the Scleroderma Research Foundation. 

Link to paper