COLUMBUS, Ohio - Researchers in The Ohio State University Comprehensive Cancer Center have devised a new way to understand how the immune system responds to interferon alfa (IFN-a), a common treatment for malignant melanoma that sometimes involves debilitating side effects.
William Carson III, MD
The findings, reported in the Sept. 1 issue of the Journal of the National Cancer Institute, shed new light on how various components of the immune system react to immunotherapy and offer insight into how doctors might better define optimal dosing to lessen the toxicity of treatment with immunotherapy.
“We’ve known for years that interferon alfa can boost a patient’s immune system, but we really haven’t understood some of its molecular targets until now,” says Dr. William Carson, director of clinical research at the OSU Comprehensive Cancer Center (OSUCCC) and senior author of the study.
Interferon alfa slows tumor growth and blocks the formation of new blood vessels tumors need to grow and spread. When IFN-a enters the body at the cellular level, one of the first gatekeepers it activates is a protein called STAT1 (signal transducer and activator of transcription 1). Interferon causes STAT1 to go through a chemical change called phosphorylation, a process that leads to widespread gene expression throughout the cell that regulates immune response.
Carson, along with Dr. Gregory Lesinski, a postdoctoral fellow in his lab and lead investigator of the project, were interested in discovering which cellular subsets of the immune system – T cells, B cells, monocytes or natural killer (NK) cells - were most responsive to IFN-a therapy.
Researchers drew blood from healthy subjects and patients with melanoma and exposed it to different levels of IFN-a. Utilizing specially designed antibodies coupled with fluorescent tags, the research team was able to sort and track STAT1 phosphorylation throughout the immune system. They found that phosphorylated STAT1 levels increased in all immune system subsets as the concentration of IFN-a rose, but that relatively low levels of IFN-a seemed to be enough to generate maximal STAT1 activation. They also discovered that compared with melanoma patients, healthy people had higher resting levels of phosphorylated STAT1 in T cells and NK cells.
Carson says the study is important for patients and researchers alike.
“For patients, it means that we now have a way we can measure their individual immune system is responding to IFN-a therapy. Patients appear to differ widely on how much interferon they may need to spark the best response. Interestingly, our findings show that more may not be better.”
Lesinski says the new flow cytometry system is fast, highly quantitative and extremely sensitive. “Using older methods, we would have had to conduct studies on each cellular subset individually. But now we can do it all with just one blood draw. This is easier, more efficient, and less burdensome for the patient.”
Sri Vidya Kondadasula, Tim Crespin, Lei Shen, Kari Kendra and Michael Walker at Ohio State also contributed to the study.
The National Institutes of Health, a National Research Service Award and a grant from The Ohio State University Department of Surgery supported the project.
The Ohio State University Comprehensive Cancer Center is a network of interdisciplinary research programs with over 200 investigators in 13 colleges across the OSU campus, the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Children’s Hospital, in Columbus. OSUCCC members conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding.# # #
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