City of Hope Team Identifies Immune Pathway Behind Radiation Lung Damage

More than 70% of lung cancer patients undergo radiation therapy at some point, and up to 20% of them emerge with debilitating breathing difficulties that can leave them dependent on supplemental oxygen. A City of Hope-led team has now identified an immune pathway in mice that drives this damage — and shown that blocking a single signaling protein can reduce the injury.

The study, published in Nature Communications and led by Heather McGee, MD, PhD, an assistant professor in the departments of radiation oncology and immuno-oncology at City of Hope, traces radiation-induced lung injury (RILI) to a transformation among rare immune cells called innate lymphoid cells (ILCs). It is the first demonstration that radiation reprograms these cells rather than only the better-studied T cells.

"Many researchers in our field study how radiation activates well-known immune cells such as T cells to fight cancer," McGee said. "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."

What did the researchers actually measure?

The team built a mouse model of localized lung irradiation and applied a layered analytical workflow: flow cytometric characterization of ILC subsets and cytokine production, single-cell transcriptomic profiling, and pseudotime analyses to reconstruct how ILC phenotypes shift after exposure. Adoptive transfer experiments then tested whether one subset acquires the features of another in vivo.

The measured result was striking. Radiation pushed protective ILC2 cells — which help guard lung tissue — into an ILC1-like identity that promotes inflammation. The driver, the researchers showed, is interferon-beta (IFN-β), whose levels rose after irradiation and acted as the switch controlling the transformation.

Crucially for translational relevance, the authors report that tests on human ILCs showed similar biological changes. The human validation, however, remains in vitro; the intervention data come from mice.

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

Does blocking the pathway work?

In mice, yes. The investigators disrupted IFN-β signaling during radiation and measured three outcomes: reduced inflammation, limited lung injury, and decreased fibrosis — the permanent scarring that can compromise lung function for life. Their paper specifies that inhibiting the plasticity by blocking IFNAR1 signaling alleviated lung damage in mouse models.

"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.

The stakes for portfolio decisions are concrete. The authors note that lung cancer accounts for about 18% of all cancer-related deaths worldwide, and radiation plays a critical role in its treatment. RILI, pneumonitis and radiation-induced lung fibrosis constrain dosing and can permanently narrow future treatment options for patients.

What separates measurement from projection?

The demonstrated facts: ILC2-to-ILC1 plasticity occurs after high-dose, restricted-field radiation in mice; type I interferon mediates the shift; comparable changes appear in human ILCs in vitro; and IFNAR1 blockade mitigates injury in mice.

The projections are the team's own. If the approach proves effective in people, the authors suggest, it could protect patients from long-term lung damage, expand radiation options for individuals with chronic lung conditions such as COPD, and permit more aggressive radiation treatment when clinically warranted.

"In conclusion, our study identifies an immune regulatory mechanism whereby type I IFN-induced ILC2-to-ILC1 plasticity contributes to the pathogenesis of RILI," the investigators wrote in their paper. "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."

The next step is human validation of IFN-pathway blockade as a radioprotective strategy, a question the mouse data now frame but do not answer.