New Research Uncovers Immune Mechanism Driving Radiation-Induced Lung Injury
Researchers at City of Hope®, one of the largest and most advanced cancer research and treatment organizations in the United States, have identified an immune signaling pathway that may contribute to radiation-induced lung injury and demonstrated a potential strategy to reduce this damage in preclinical studies. Published in Nature Communications, the research reveals how radiation can alter the behavior of specific immune cells, turning cells that normally help protect the lungs into drivers of inflammation and tissue injury.
The findings could support the development of new approaches to protect healthy lung tissue during cancer treatment, potentially reducing long-term respiratory complications and improving patients’ quality of life. The study focuses on innate lymphoid cells (ILCs), a group of immune cells that help regulate tissue health and immune responses, and identifies interferon-beta (IFN-β) as a key signaling protein involved in radiation-induced changes to these cells.
Radiation therapy remains an important treatment option for many patients with cancer, including those with lung cancer. However, although radiation can destroy cancer cells and control tumor growth, it can also affect nearby healthy tissues. When the lungs are exposed to radiation, the resulting injury may lead to inflammation, breathing difficulties and fibrosis, a process in which damaged tissue becomes scarred.
According to the research announcement, approximately 230,000 Americans are diagnosed with lung cancer each year, and up to 70% of people diagnosed with the disease will receive radiation at some point during their treatment. For some patients, radiation-related lung damage can become a persistent complication that affects daily activities, limits future treatment options and reduces overall quality of life. Up to 20% of patients may experience debilitating breathing difficulties associated with lung injury.
The City of Hope research team sought to understand why radiation damages healthy lung tissue and whether specific immune mechanisms could be targeted to prevent or reduce these effects. Their findings identify a previously underrecognized role for ILCs in radiation-induced lung injury and suggest that interfering with IFN-β signaling could help limit inflammation and fibrosis.
Radiation Changes the Behavior of Protective Immune Cells
The study was led by a research team under the direction of Heather McGee, M.D., Ph.D., corresponding author and an assistant professor in the departments of radiation oncology and immuno-oncology at City of Hope.
Much of the existing research examining the relationship between radiation and the immune system has focused on well-characterized immune cells, including T cells, which play important roles in recognizing and attacking cancer cells. However, the City of Hope team investigated whether less frequently studied immune cell populations also contribute to the effects of radiation on healthy tissue.
“Many researchers in our field study how radiation activates well-known immune cells such as T cells to fight cancer,” said McGee. “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.”
To investigate the biological mechanisms underlying radiation-induced lung injury, McGee and her colleagues developed a mouse model designed to examine how radiation affects healthy lung tissue and the immune cells residing within it.
The researchers used advanced techniques to track changes in immune cell behavior following radiation exposure. Their analysis revealed that radiation could substantially alter the identities and functions of innate lymphoid cells, providing insight into how the immune response may contribute to tissue damage after treatment.
Under normal conditions, different types of ILCs help maintain tissue health, coordinate immune responses and regulate inflammation. Their functions depend on the specific cell type and the signals they receive from their surrounding environment.
The researchers found that radiation exposure caused one population of these cells, known as group 2 innate lymphoid cells (ILC2s), to undergo a transformation into cells resembling group 1 innate lymphoid cells (ILC1s).
This change is significant because ILC2s and ILC1s perform different biological functions. ILC2s can contribute to protective responses in the lungs, while ILC1s are associated with inflammatory activity. According to the study, radiation-induced changes in these cells may shift the immune environment toward inflammation that damages healthy lung tissue.
The findings suggest that radiation-related lung injury is not solely a direct consequence of radiation exposure to healthy cells. Changes in the behavior of the immune system may also contribute to the progression of tissue damage.
Understanding these immune responses could help researchers identify ways to preserve healthy tissue while maintaining the therapeutic benefits of radiation against cancer.
Interferon-Beta Identified as a Key Driver of Immune Cell Transformation
After identifying the changes in ILC populations, the research team investigated the molecular signals responsible for driving this transformation.
The researchers found that radiation increased levels of interferon-beta, or IFN-β, a signaling protein involved in regulating immune responses. Their experiments indicated that IFN-β acted as an important trigger for the transition of protective ILC2s into inflammatory ILC1-like cells.
This observation provided a potential explanation for how radiation exposure could initiate a sequence of immune changes that contribute to lung injury.
IFN-β belongs to the type I interferon family of signaling proteins, which play important roles in immune regulation. These proteins help cells respond to environmental threats and coordinate different aspects of immune activity. However, immune signaling can have different effects depending on the biological context, the duration of the response and the tissues involved.
In the setting investigated by the City of Hope team, increased IFN-β signaling appeared to promote a change in ILC identity and function that favored inflammation rather than tissue protection.
The researchers also examined human innate lymphoid cells and observed similar biological changes, supporting the relevance of the mechanism beyond the mouse model. Although these findings do not establish that the same pathway drives lung injury in patients undergoing radiation therapy, they provide additional evidence for investigating IFN-β signaling in human disease.
“Much like a player switching teams, radiation-induced IFN-beta 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.”
The identification of IFN-β as a potential driver of ILC transformation provides researchers with a specific pathway to investigate when developing strategies to reduce radiation-related complications.
Rather than attempting to suppress the immune system broadly, future therapeutic approaches could potentially focus on interrupting the signals responsible for harmful immune cell changes. However, further research will be needed to determine how such interventions could be delivered safely and whether they would preserve the immune activities required for effective cancer treatment.
Blocking IFN-β Signaling Reduced Lung Injury in Preclinical Studies
Having identified the signaling pathway associated with immune cell transformation, the research team next investigated whether blocking IFN-β signaling could prevent or reduce radiation-induced lung damage.
In experiments involving mice, the researchers disrupted the signaling pathway during radiation exposure and evaluated the effects on inflammation and lung tissue injury.
The results indicated that interfering with IFN-β signaling reduced inflammation, limited lung injury and decreased fibrosis in the affected tissue.
Fibrosis is a major concern in radiation-induced lung injury because it involves the formation of scar tissue that can interfere with normal lung function. As fibrosis progresses, healthy tissue may become less flexible, reducing the lungs’ ability to expand and contract efficiently during breathing.
For patients who develop significant radiation-related fibrosis, respiratory complications may persist long after cancer treatment has ended. These effects can be especially challenging for individuals who already have reduced lung function or other respiratory conditions.
The reduction in inflammation and fibrosis observed in the preclinical experiments suggests that targeting IFN-β signaling could potentially address important biological processes involved in the development of radiation-induced lung injury.
Jaeho Kim, M.D., Ph.D., first author of the study and a radiation oncology postdoctoral fellow at City of Hope, highlighted the potential significance of the findings.
“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,” Kim said.
The results establish a basis for additional research into the therapeutic potential of blocking this pathway. Nevertheless, the experiments were conducted in a preclinical setting, and the approach has not yet been established as a treatment for patients receiving radiation therapy.
Future studies will need to determine whether the protective effects observed in mice can be reproduced in humans, identify the most appropriate timing and method of pathway inhibition, and assess potential effects on cancer control and normal immune function.
Potential to Improve Quality of Life for Patients Receiving Radiation
If further studies demonstrate that IFN-β pathway inhibition is safe and effective in humans, the approach could help address a significant complication associated with radiation therapy.
For patients with lung cancer, preserving healthy lung tissue is particularly important because treatment may involve radiation directed near critical respiratory structures. Reducing damage to surrounding tissue could potentially help patients maintain lung function and avoid some of the long-term consequences of treatment.
A strategy that reduces radiation-related inflammation and fibrosis could also have implications for patients with other cancers when radiation fields involve lung tissue. The potential relevance would depend on the treatment setting, the extent of lung exposure and the underlying risk of injury.
The research team also identified possible implications for patients with pre-existing respiratory conditions, including chronic obstructive pulmonary disease (COPD).
COPD is a chronic lung condition associated with airflow limitation and reduced respiratory capacity. Patients with compromised lung function may face additional challenges when treatment decisions involve therapies that can affect healthy lung tissue.
If an effective protective intervention can be developed, it could potentially expand treatment options for selected patients whose underlying lung conditions complicate radiation planning. It may also help researchers investigate whether radiation can be delivered more effectively in circumstances where the risk of lung injury currently limits treatment choices.
However, the study does not establish that patients with COPD or other chronic lung diseases would benefit from IFN-β inhibition. Clinical investigations would be required to determine which patients might be appropriate candidates and whether the benefits outweigh the risks.
The findings also highlight the importance of balancing tissue protection with cancer treatment effectiveness. Radiation therapy is designed to damage cancer cells, and any intervention intended to protect healthy tissue must be evaluated carefully to ensure it does not compromise tumor control or produce unintended effects.
City of Hope Builds on Its Cancer Immunotherapy Research
The study adds to City of Hope’s broader research efforts in radiation oncology, immuno-oncology and the development of innovative cancer treatments.
The organization has a longstanding focus on understanding interactions between cancer cells and the immune system, including the development of immunotherapies intended to harness immune responses against tumors.
City of Hope reports that it is the only institution with four FDA-authorized clinical trials using genetically reprogrammed T cells. The organization has also pioneered the use of reengineered T-cell therapies for lymphoma, malignant brain tumors and neuroblastoma in children.
In addition, City of Hope has contributed to the development of cancer radioimmunotherapy, an approach that uses monoclonal antibodies to direct radiation toward tumors.
Its Center for Biomedicine & Genetics supports research and manufacturing activities intended to facilitate the translation of emerging immunotherapies into clinical trials.
The latest findings reflect another dimension of the organization’s research: understanding how cancer treatments affect healthy tissues and identifying strategies that could reduce treatment-related complications.
By investigating the immune mechanisms responsible for radiation-induced lung injury, the researchers are exploring how a more detailed understanding of biological responses to treatment could lead to approaches that improve both the safety and effectiveness of cancer care.
Study Published in Nature Communications
The research was published in Nature Communications under the title “Type I IFN promotes ILC2-to-ILC1 plasticity in pre-clinical radiation-induced lung injury.”
The study received funding through grants from the National Cancer Institute, including R00CA256526 and P30CA033572; the National Institutes of Health, through grant K24AI171795; and the Veterans Affairs Office of Research and Development, through grant BX005073.
The authors noted that the content of the research is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Overall, the study identifies a potential connection between radiation exposure, IFN-β signaling and the transformation of innate lymphoid cells that may contribute to healthy lung tissue damage. By demonstrating that disruption of this pathway reduced inflammation, lung injury and fibrosis in mice, the researchers have established a foundation for further investigation.
Although clinical validation remains necessary, the findings could inform future approaches to preventing radiation-induced lung complications. Continued research will determine whether targeting IFN-β signaling can ultimately help patients receive effective cancer treatment while preserving healthy lung function and improving long-term quality of life.
About City of Hope
City of Hope’s mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the United States, and one of the leading research centers for diabetes and other life-threatening illnesses.
City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked among the nation’s top cancer centers by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work.
City of Hope’s growing national system includes its Los Angeles campus, Orange County, California, campus, a network of clinical care locations across Southern California and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas.