Cancer immunotherapy may offer new way to treat IPF: Mouse study
Ipilimumab found to reduce scar formation, promote tissue regeneration
A cancer immunotherapy known as ipilimumab was able to reduce scar formation and promote tissue regeneration in the lungs of a mouse model of idiopathic pulmonary fibrosis (IPF).
Treatment boosted the immune system’s ability to clear senescent cells, or those that no longer divide or grow but accumulate in the lungs of IPF patients, thereby promoting inflammation and scarring.
“This opens up an entirely new direction for potential treatment of IPF,” Santu Yadav, PhD, the study’s lead author and assistant professor of medicine at Tulane University School of Medicine, in Louisiana, said in a university news story. “Instead of using drugs to kill senescent cells, we are re-activating our own immune system to clear them out.”
The discovery was detailed in a study, “Reactivation of CTLA4-expressing T cells Accelerates Resolution of Lung Fibrosis in a Humanized Mouse Model,” published in The Journal of Clinical Investigation.
Immune system normally helps clear old cells to make room for new ones
Senescent cells have lost their ability to divide and function properly. Under normal circumstances, the immune system helps clear these old cells to make room for new, healthy ones.
In people with IPF, however, senescence markers are more abundant than in healthy individuals, and the abnormal persistence of these cells has been linked to inflammation and scar tissue formation.
As a result, recent research has focused on developing senolytic agents, or therapies that target and kill senescent cells, to treat progressive fibrotic disorders, such as IPF. However, the reason why these cells persist and are not cleared by the immune system remains unknown.
To find out, a research team led by Victor Thannickal, MD, senior study author and professor of medicine at Tulane, examined gene activity and protein production in lung tissues from IPF patients.
The team discovered that, next to regions of fibrosis, there were high levels of the CTLA4 protein on a type of immune cell known as CD8-positive T-cells, also called cytotoxic T-cells.
Cytotoxic T-cells function to eliminate damaged cells from tissues and organs, while CTLA-4, a type of immune checkpoint protein, helps prevent excessive inflammation by suppressing overactive T-cells. Similar findings were seen when the lungs of mice with induced pulmonary fibrosis were examined.
“The CTLA4 protein normally functions to prevent excessive inflammation by blocking overactive T cells,” Thannickal said. “Too much of this ‘blocker protein’ may result in losing the ‘good’ inflammation that is needed to remove senescent cells.”
To determine the potential role of CTLA4 in lung fibrosis, the researchers treated IPF mice with ipilimumab. The mice had been modified to produce a portion of human CTLA4. The approved cancer immunotherapy, sold under the brand name Yervoy, binds to CTLA4 and helps the immune system recognize and destroy cancer cells more effectively.
“What we’re doing is blocking the blocker,” Thannickal said.
Ipilimumab-treated mice showed reduced fibrosis
Ipilimumab-treated mice showed reduced fibrosis, as indicated by lower levels of markers for scar tissue formation. At the same time, there were signs of tissue regeneration, as demonstrated by a substantial increase in the number and percentage of alveolar epithelial type 2 cells. These cells line the tiny air sacs in the lungs and can act as a source of new airway cells. There were also more cytotoxic T-cells and a subpopulation expressing CTLA4 following ipilimumab treatment.
The team then confirmed that activating cytotoxic T-cells with ipilimumab reduced the number of senescent cells in lung tissues of mice with pulmonary fibrosis.
These findings demonstrate “the cytotoxic effects of [CD8-positive] T cells on senescent cells and their improved killing efficiency when CTLA4 is inhibited,” suggesting that “impaired immune-mediated clearance of these cells contribute to persistence of lung fibrosis in this murine model,” the researchers wrote.
This treatment strategy may also help with aging diseases marked by the buildup of senescent cells, such as cardiovascular disease or Alzheimer’s disease.
“If it works in IPF, this immune rejuvenating approach to treatment may be effective in other diseases such as Alzheimer’s or cardiovascular diseases in which senescent cells are known to accumulate,” Thannickal said. “Can the right drug activate T cells in a way that clears senescent cells without causing collateral damage? If so, we may be closer to combating many aging related diseases and perhaps even aging itself.”
Because lung inflammation has been associated with the use of CTLA4-targeted therapies, “caution must be exercised when re-purposing immune checkpoint blockade therapies in chronic lung inflammatory and fibrotic diseases,” the researchers wrote.
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