Scientists discover immune pathway behind radiation-induced lung damage

Researchers at City of Hope^®, one of the largest and most advanced cancer research and treatment organizations in the country, have uncovered an immune pathway that may contribute to radiation-related lung damage and have identified a potential strategy to block it. Published today in Nature Communications, the insights from the preclinical study could lead to new treatments that prevent radiation from harming healthy lung tissue and improve patients' quality of life.

Some 230,000 Americans are diagnosed with lung cancer each year, and up to 70% of people diagnosed with the disease will undergo radiation at some point in their treatment. While radiation is often lifesaving, the therapy can permanently damage healthy lung tissue and limit future cancer treatment options.

When healthy lung tissue is damaged, the effects can be severe and long-lasting. Up to 20% of patients struggle with debilitating breathing difficulties and reduced quality of life, leaving some patients tethered to heavy oxygen tanks.

Radiation reprograms rare but important immune cells

Many researchers in our field study how radiation activates well-known immune cells such as T cells to fight cancer. We are the first group to show that radiation also reprograms rare immune cells called innate lymphoid cells, and that these cells play a key role in driving damage to healthy lung tissue."

Heather McGee, M.D., Ph.D., corresponding author, assistant professor, departments of radiation oncology and immuno-oncology, City of Hope

Dr. McGee leads a team of scientists investigating the role innate lymphoid cells play in the response to radiation. To better understand how radiation damages healthy lung tissue, her laboratory developed a mouse model of radiation-induced lung injury.

Using advanced techniques to track radiation's impact on the immune system, her team observed three key findings.

First, radiation provoked a dramatic transformation in innate lymphoid cells (ILCs), causing them to adopt different identities and alter their functions. One type of ILC, called ILC2s, helps protect the lungs from damage. Radiation transformed these cells into another type, called ILC1s, which promotes inflammation that damages healthy lung tissue.

Second, the researchers discovered what drives this transformation. Radiation increased levels of a signaling protein called interferon-beta (IFN-beta), which acted as the switch that pushed protective ILC2 cells to become inflammatory ILC1 cells. Tests on human ILCs showed similar biological changes.

"Much like a player switching teams, radiation-induced IFN-beta can shift these immune cells from a protective role to one that promotes inflammation," Dr. McGee said. "Our findings shed light on a previously unknown mechanism that leads to radiation-induced lung damage."

A potential strategy to prevent lung damage during radiation

Third, the researchers tested whether blocking the IFN-beta signaling pathway during radiation could stop the harmful immune cell transformation. In mice, disrupting this pathway reduced inflammation, limited lung injury and decreased the fibrosis that can permanently scar healthy lung tissue.

"Our findings suggest that high levels of IFN-beta contribute to the development of lung damage during radiation and that blocking this signaling pathway could offer a potential treatment to reduce this debilitating side effect," said Jaeho Kim, M.D., Ph.D., first author of the study and a radiation oncology postdoctoral fellow at City of Hope.

If the team's approach proves effective in people, it could protect patients from long-term lung damage, expand radiation options for individuals with chronic lung conditions like chronic obstructive pulmonary disease (COPD) and enable more aggressive radiation treatment when needed.

A leader in cancer immunotherapeutics and tumor immunology research

City of Hope is the only institution with four FDA-authorized clinical trials using genetically reprogrammed T cells and is the first center to use reengineered T cell therapy for lymphoma, malignant brain tumors and neuroblastoma in children.

City of Hope pioneered cancer radioimmunotherapy, a therapeutic strategy in which radiation is targeted to tumors using monoclonal antibodies. Its Center for Biomedicine & Genetics empowers researchers to speed the translation of new immunotherapies into clinical trials.