Radiotherapy Reprograms Immune Response in Cutaneous T-Cell Lymphoma, Revealing New Biomarkers for Recurrence
Key Insights
A Northwestern Medicine study reveals that radiotherapy (search) fundamentally reshapes the immune ecosystem within cutaneous T-cell lymphoma (search) (CTCL) tumors beyond simply killing cancer cells.
Researchers used spatial transcriptomics and a novel non-invasive skin tape-strip method to track molecular changes before and after radiotherapy (search) in CTCL patients.
Tumors that recurred within one year showed increased radiation resistance genes and persistent inflammation, while remission tumors exhibited stronger interferon signaling and sustained humoral immune activation.
A new Northwestern Medicine study has uncovered how radiotherapy (search) reprograms the immune microenvironment within cutaneous T-cell lymphoma (search) (CTCL) tumors, revealing molecular signatures that may predict long-term treatment response and tumor recurrence. The findings, published in the Journal of the American Academy of Dermatology, represent the first demonstration that non-invasive skin tape strips can track disease-related protein biomarkers in cutaneous lymphoma over the course of treatment.
"Our findings show that radiation does much more than kill lymphoma cells; it fundamentally reshapes the immune ecosystem surrounding the tumor," said co-senior author Alan Zhou, MD, associate professor of Dermatology and chief of the Division of Medical Dermatology at Northwestern Medicine. "Understanding these immune changes may help us predict which patients will have durable responses and identify new therapeutic strategies that enhance the long-term effectiveness of radiation."
The Challenge of CTCL Recurrence After Radiotherapy (search)
Cutaneous T-cell lymphoma (search) is a rare type of lymphoma that primarily affects the skin and is most commonly diagnosed in people over the age of 50. While radiotherapy (search) remains one of the most effective treatments for CTCL, clinical outcomes vary: many tumors remain in remission after treatment, but others recur despite an initial response. The biological mechanisms driving this divergence have remained poorly understood.
To investigate, the research team studied paired skin biopsy samples and non-invasive skin tape-strip samples collected from CTCL patients both before and after radiotherapy (search). The novel tape-strip approach involves applying a round piece of specialized tape onto a patient's lesional tumors multiple times, capturing protein biomarkers expressed on the skin's surface.
"This is the first study to show that we can use painless tape strips to track disease-related protein biomarkers in cutaneous lymphoma over the course of treatment," Zhou said. "That could one day make it much easier to monitor patients and personalize their care."
Immune Landscape Transformation
Using spatial transcriptomics and high-dimensional proteomics techniques, the scientists characterized gene expression within the tumor microenvironment while measuring proteins released from the skin. Before radiotherapy (search), tumors exhibited molecular hallmarks of CTCL, including inflammatory signaling, exhausted T-cells, and macrophages promoting tumor growth.
After radiotherapy (search), the immune landscape changed significantly. The researchers observed decreased tumor-associated inflammatory pathways, increased wound-healing programs, and innate immune activation. Unexpectedly, they also detected activation of humoral immune pathways involving antibody-producing immune cells.
"These results suggest that antibody-mediated immunity may play a much larger role in anti-tumor responses than previously appreciated," said Zhou, who is also a member of the Robert H. Lurie Comprehensive Cancer Center (search) of Northwestern University.
Predicting Recurrence Through Molecular Signatures
The study identified key molecular differences between patients whose tumors remained in remission and those whose tumors recurred within one year of treatment. Tumors that recurred demonstrated increased expression of genes associated with radiation resistance and persistent inflammation. In contrast, tumors that remained in remission exhibited stronger interferon signaling and sustained humoral immune activation following radiotherapy (search).
These findings suggest that molecular biomarkers could help identify CTCL tumors at greater risk of recurrence earlier, enabling more proactive clinical decision-making.
Toward Non-Invasive Monitoring and Precision Medicine
The study demonstrates the feasibility of using non-invasive skin tape strips for monitoring longitudinal molecular changes within a tumor, allowing patients to be observed over time without repeated skin biopsies.
"Patients with cutaneous lymphoma often undergo multiple biopsies throughout the course of their disease," Zhou said. "Our findings suggest that non-invasive tape strips may provide a practical way to repeatedly monitor disease-relevant biomarkers over time. We envision a future where we can combine molecular profiling of tumors with simple skin sampling to personalize treatment decisions and track how patients are responding."
Zhou noted that the current study opens new opportunities to develop combination therapies that enhance anti-tumor immunity while bringing precision medicine closer to routine clinical care.
The study was co-senior authored by Ziyou Ren, PhD, assistant professor of Dermatology and of Preventive Medicine in the Division of Epidemiology. Co-lead authors included JoJo Holm, a clinical research coordinator; Eleanor Ostroff, a clinical research fellow; and Lauren Clarke, MD, all from the Department of Dermatology. The research was supported by the Dermatology Foundation, Cutaneous Lymphoma Foundation, American Cancer Society, Lymphoma Research Foundation, Gilead Research Scholars Program, and philanthropic support from private donors.