Corticosteroids, commonly prescribed to manage cancer-related symptoms in non-small cell lung cancer patients receiving immunotherapy, have been identified as the primary factor behind immunotherapy treatment failures, according to groundbreaking research from Keck Medicine of USC published in Cancer Research Communications.
The study analyzed 277 patients with Stage II-IV non-small cell lung cancer treated with immune checkpoint inhibitors (ICIs) and found that high doses of steroids administered before and during immunotherapy significantly reduced treatment effectiveness. Patients receiving steroids experienced less tumor shrinkage and shorter survival times compared to those not on steroid therapy.
"Steroids were the biggest predictor of why certain immunotherapies may not be effective, even when considering multiple other factors such as stage and progression of the disease," said Dr. Fumito Ito, lead author and Keck Medicine oncologist and immunologist.
Mechanism Behind Treatment Interference
The research team uncovered the biological mechanism explaining why steroids compromise immunotherapy effectiveness. Their findings reveal that corticosteroids prevent the body's natural cancer-fighting T-cells from reaching full maturity, significantly impairing their ability to attack cancer cells.
"Our findings reveal that steroids stop the body's natural cancer-fighting cells, T-cells, from maturing. This makes them unable to attack the cancer as vigorously as they usually would, leading to worse outcomes for patients," explained Dr. Ito, who also serves as a member and co-leader of the translational and clinical sciences research program at USC Norris Comprehensive Cancer Center.
The researchers conducted preclinical studies using mouse models to observe the effects of steroids on ICI therapy in real time, confirming that steroids given before or during immunotherapy inhibit T-cell maturation.
Impact on Treatment Monitoring
Beyond affecting T-cell function, the study discovered that steroids block circulating biomarkers in the bloodstream—cellular fragments that signal cancer progression and help oncologists adjust treatment strategies. This interference creates a double burden for patient care.
"Without the presence of circulating biomarkers to inform our decisions, oncologists cannot treat the cancer as effectively and patients may miss out on the best treatment for their cancer," Dr. Ito noted.
Clinical Implications and Treatment Considerations
The research examined the interaction between corticosteroids and immune checkpoint inhibitors, which help the body's immune system fight cancer by blocking proteins that prevent T-cells from attacking cancer cells. ICIs are frequently used to treat non-small cell lung cancer, the most common form of lung cancer.
Steroids are typically prescribed to alleviate various cancer-related symptoms including fatigue, vomiting, brain swelling, and lung inflammation. These medications work by suppressing the immune system, which reduces inflammation but creates a therapeutic conflict with immunotherapy approaches.
The retrospective study analyzed up to eight years of medical records from patients treated at three centers, including USC Norris Comprehensive Cancer Center, comparing outcomes between patients prescribed steroids and those who were not.
Balancing Treatment Needs
While the findings demonstrate clear interference between steroids and immunotherapy, researchers acknowledge the continued importance of corticosteroids in cancer care. Dr. Ito emphasized that for some patients, steroids remain necessary to manage cancer-related symptoms.
"We know that steroids will continue to play an important role in lung cancer care, but it is important to understand their potential limitations," said Dr. Ito. "Each patient should talk to their oncologist to make sure they have the best possible care plan tailored to their specific needs."
The research team hopes their findings will stimulate additional studies examining steroid effects on immunotherapy, enabling oncologists to make more informed treatment decisions that optimize patient outcomes.
The study was conducted by Dr. Ito along with Keck Medicine medical oncologists Dr. Jorge Nieva and Dr. Robert Hsu, with support from multiple grants including the National Cancer Institute, Department of Defense Lung Cancer Research Program, and the Uehara Memorial Foundation.
