Immune Pathway Contributing to Radiation Therapy-Related Lung Damage Identified in Mice

More than 70% of people diagnosed with lung cancer will undergo radiation therapy (RT) at some point in their treatment, but while such therapy is often lifesaving, it can permanently damage healthy lung tissue and limit future cancer treatment options.

Working with a mouse model of radiation-induced lung injury (RILI) researchers headed by a team at City of Hope have uncovered an immune pathway that may contribute to radiation-related lung damage, which may point to a potential preventive strategy. The researchers suggest that insights from their preclinical study could lead to new treatments that prevent radiation therapy from harming healthy lung tissue and so improve patients’ quality of life.

Research lead Heather McGee, MD, PhD, an assistant professor in the departments of radiation oncology and immuno-oncology at City of Hope, said, “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.” McGee is corresponding author of the team’s published paper in Nature Communications, titled “Type I IFN promotes ILC2-to-ILC1 plasticity in pre-clinical radiation-induced lung injury.”

Lung cancer is one of the leading causes of cancer-related mortality worldwide, accounting for about 18% of all cancer-related deaths, the authors wrote, and radiation therapy (RT) plays a critical role in the treatment of patients with lung cancer. However, they noted, “Although RT can cure patients with lung cancer, it can also lead to severe complications, such as radiation-induced lung injury (RILI), pneumonitis, and radiation-induced lung fibrosis (RILF).”

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. “RILI can significantly impair lung function, often leading to supplemental oxygen dependence,” the team added. McGee leads a team of scientists investigating the role that innate lymphoid cells play in the response to radiation.

To better understand how radiation damages healthy lung tissue the researchers developed a mouse model of radiation-induced lung injury and focused their studies on the potential role of innate lymphoid cells (ILCs). “While ILCs have been implicated in the pathogenesis of various lung diseases, their contribution to RILI has not been investigated,” they noted in their report. “In this study, we evaluate how high-dose, restricted field radiation therapy affects lung ILC function and plasticity in the context of RILI.”

The team used a number of techniques to track radiation’s impact on the immune system. “Using a mouse model of localized lung irradiation, we combine flow cytometric characterization of ILC subsets and cytokine production with single-cell transcriptomic and pseudotime analyses to define radiation associated changes in ILC phenotype and function, they explained. “We further use adoptive transfer experiments to determine whether ILC2s acquire ILC1-like features after irradiation in vivo.”

Their results showed that radiation provoked a dramatic transformation of ILCs causing them to adopt different identities and altering their functions. One type of ILC, called ILC2s, helps protect the lungs from damage. Radiation transformed these cells into another type, ILC1s, which promote inflammation that damages healthy lung tissue.

The researchers also discovered what drives this transformation, showing that radiation increased levels of the signaling protein interferon-beta (IFN-β), which acted as the switch that pushed protective ILC2 cells to become inflammatory ILC1 cells. Tests on human ILCs showed similar biological changes. “These findings identify radiation-induced type I interferon-mediated ILC plasticity as a mechanism underlying the pathogenesis of RILI,” the investigators noted.

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

The investigators in addition tested whether blocking the IFN-β signaling pathway during radiation could stop the harmful immune cell transformation. The found that 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 first author Jaeho Kim, MD, PhD, 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 such as chronic obstructive pulmonary disease (COPD), and enable more aggressive radiation treatment when needed. In their paper the team stated, “In conclusion, our study identifies an immune regulatory mechanism whereby type I IFN-induced ILC2-to-ILC1 plasticity contributes to the pathogenesis of RILI,” they concluded. “We also demonstrate that inhibiting this plasticity by blocking IFNAR1 signaling can alleviate lung damage in mouse models, offering a potential therapeutic strategy to minimize the side effects of radiation therapy in patients.”

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