Immune checkpoint inhibitors strengthen the immune response against cancer cells, but the medications are ineffective against certain tumors. Results from a new clinical trial indicate that adding radiation may overcome this resistance to immune checkpoint inhibitors.
- This study uncovers the function of CD4+ T cells found in moles and a novel strategy for activating them that could strengthen the antitumor response and overcome obstacles to current immunotherapies.
- The road to an effective melanoma prevention and treatment could involve suppressing Tregs, immune cells that block the activity of CD4+ T cells in the mole.
Shadmehr (Shawn) Demehri, MD, PhD
Our research found that moles – those flat brown spots that all of us have – are infiltrated by T cells that are primed to destroy the mole.
Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital
BOSTON – Researchers at Massachusetts General Hospital (MGH) have found that a subset of white blood cells known as CD4+ T cells reside naturally in moles on the body and could be activated as part of a novel strategy to treat melanoma and generate a potent immunity against its recurrence. The team learned that common moles are immunogenic targets for killer CD4+ T cells which, through their activation, could potentially broaden the body’s antitumor response and overcome the obstacles to current cancer immunotherapies, such as checkpoint inhibitors. The results of the study were published in Science Advances.
“Our research found that moles – those flat brown spots that all of us have – are infiltrated by T cells that are primed to destroy the mole,” says senior author Shadmehr (Shawn) Demehri, MD, PhD, an investigator in the Center for Cancer Immunology and the Cutaneous Biology Research Center at MGH. “These killer immune cells could be activated by immune-based therapeutics to not only eradicate the mole and the melanoma, but also generate a larger pool of immune cells that could help protect the individual against future development and progression of the cancer.” Activating resident CD4+ T cells, he adds, could be especially important for high-risk populations, including people with many atypical moles, or those with a family history or their own history of melanoma.
Melanoma, among the most serious forms of skin cancer, originates from melanocytes – cells that produce melanin, the pigment that gives skin its color. Approximately one-third of melanomas begin in moles, the rest from normal-looking skin. The MGH team sought to understand the relationship between melanocytic nevi – essentially, moles with few mutations – and melanoma. What they found was that once benign moles from humans were transplanted into immunodeficient mice in the lab, the moles were suddenly rejected or killed by the CD4+ T cells.
“In humans, the moles were not being rejected because they were held in check by other immune cells known as Tregs, or immunosuppressive regulatory T cells,” explains first author Erik Schiferle, an investigator in the Center for Cancer Immunology and the Cutaneous Biology Research Center. “Once in mice, however, the Tregs were inactive because they lacked the signaling present in humans. Without the suppressive effect of Tregs, the CD4+ T cells were free to become activated and eliminate the mole. This biological cause and effect suggested to us that if you could block the Tregs that already exist in human moles, you could reactivate the anti-melanocyte CD4+ T cells to eliminate the mole while cross-protecting the patient against the melanoma developing and/or reappearing.”
The study suggests that the next important step could be development of a treatment to suppress the Tregs at the site of the mole. Research is in fact under way in a number of labs on agents that could suppress Tregs to combat a variety of cancers. “One potential therapeutic approach is a localized or topical agent that could be applied on the skin to eradicate the mole,” says Schiferle. “Through our work, we’ve enlightened the field that Tregs are an appropriate target for immunosuppression of killer immune cells in the moles, and melanoma specifically.”
Just as important, the study highlighted the role of CD4+ T cells, which typically don’t get the recognition of CD8+ T cells, the body’s dominant antitumor cell type. “We believe they are as important as CD8+ T cells, if not more so, in rejecting their target, which in this case is a mole that could potentially lead to melanoma,” notes Demehri, a dermatologist. “Our lab is also investigating the role of CD4+ T cells in breast cancer, lung cancer, and other carcinomas as science begins to appreciate these immune cells as active and versatile players in both cancer treatment and immunoprevention.”
Demehri is associate professor in the Department of Dermatology at Harvard Medical School and director of the High Risk Skin Cancer Clinic at MGH. Schiferle is an investigator and PhD candidate in the Center for Cancer Immunology and the Cutaneous Biology Research Center. Other co-authors include Ryan Sullivan, MD, with the Division of Hematology and Oncology at MGH; Se Yun Cheon and Heehwa Son, PhD, with the Center for Cancer Immunology and the Cutaneous Biology Research Center; and Seokjin Ham, PhD, with the Department of Biological Sciences at the Korea Advanced Institute of Science and Technology.
The research was supported by the Burroughs Wellcome Fund, the Sidney Kimmel Foundation and the National Institutes of Health.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2020, Mass General was named #6 in the U.S. News & World Report list of "America’s Best Hospitals."
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