Between the lungs and in front of the heart sits a small gland called the thymus that wields incredible power over human health by producing T cells, key components of our immune system. In cancer patients, certain therapies — along with aging and stress — can deplete T cell output, leaving individuals susceptible to infection and additional disease.
“Our discovery — the regulatory T cell recirculation back to the thymus — promotes repair through a process that hasn't been described before and represents a novel pathway to regeneration in the gland,” said lead author Andri Lemarquis, M.D., Ph.D., staff scientist and group leader of the thymus research program in the laboratory of Marcel van den Brink, M.D., Ph.D., president of City of Hope Los Angeles and National Medical Center, Deana and Steve Campbell Chief Physician Executive Distinguished Chair and senior author of the paper. “The findings open up a new translational angle for addressing thymic fatigue and damage.”
The Role of the Thymus
Over a lifetime, the human body faces a wide variety of threats from bacteria, viruses and other dangers, such as cancer. T cells, made by the thymus, fight pathogens and malignancies through direct attack or by teaching other immune cells how to remove threats.
“Because there are so many different threats out there, we need an incredible diversity of these soldiers, or immune cells, to defend us,” explained Dr. Lemarquis. “But we also need some kind of control, so we don't get a civil war in our body, like an autoimmune disease. This requires a school to teach these cells to protect us and that school is the thymus.”
Unfortunately, the thymus is highly susceptible to injury caused by stress, infections, aging and cancer therapies.
“If you receive cancer therapies, your thymus is going to shrink,” said Dr. Lemarquis. “Without some help to grow again, patients won't get what's called immune reconstitution, in which new protective T cells are produced. Our work is trying to boost the thymus in patients who might lose this basic protection.”
Finding the Key to Regeneration
Dr. Lemarquis and the research team set out to explore mechanisms of thymus regeneration in two settings, cancer therapies and aging, which go together since aging cancer patients are highly susceptible to infection. The scientists first studied treatment-related injuries in murine models to understand how the thymus is damaged and under what conditions it begins to rebound. Then, they combined imaging and analyzing techniques with machine learning to identify specific pathways that are activated during regeneration.
What they found was a novel and previously undescribed population of thymic regulatory T cells (Tregs) that accumulate in the thymus after injury and secrete a growth factor called amphiregulin. Dr. Lemarquis and his collaborators were able to show that when these Tregs were added to the bloodstream intravenously, they found their way back to the thymus where amphiregulin then helped teach the thymus to regenerate and develop more T cells. Next, they tested their findings in human tissue samples and saw the same results.
“We were able to go from mechanistic insights in mice to seeing that the same pathways were operating in the human setting,” said Dr. Lemarquis. “There are a lot of adoptive cell therapies right now in the Tregs space, so that opens up the possibility for a translational approach where this subset of Tregs can be used to regenerate tissues, and specifically in the thymus and the immune system.”
He said the researchers were also surprised to find that the results extended to older mice, too, as it was believed that lost thymic function from aging may not be treatable.
“There are recent studies that show that if you lose thymic function in aging, you will have an increased rate of mortality due to a higher rate of cancers, infections and autoimmunity,” said Dr. Lemarquis. “And what we could show was that when we transferred Tregs into aged mice receiving cancer therapies, we could even boost their function. It's not only the young thymus that can be receptive to these signals to regenerate, but even the thymus in older patients receiving cancer therapies.”
From Lab to Life
The work outlined in the Immunity paper builds on a research program established in the late 1990s by Dr. Van den Brink to boost immune reconstitution in patients receiving cancer therapies, especially in the bone marrow transplantation field.
“He laid the groundwork over decades that provided us with the models, tools and data to get to where we are today,” said. Dr. Lemarquis. “There’s also been tremendous work on regulatory T cells, and we brought together these two fields to see if there’s something therapeutic that we can do in the setting of thymic injury. But brilliant minds before us led the way.”
Next, the researchers are delving into a large atlas of human thymic samples from cancer patients of different ages who have either thymic rebound or are in the degenerative phase to understand more about which pathways might intertwine with the regulatory T cells to further improve thymic function. They are also looking for other ways to apply their findings in a human setting, for example, by potentially using synthetic biology to modify T cells to overproduce amphiregulin or other beneficial factors.
“We have a thymic research program now at City of Hope, with computational biologists and postdoctoral scholars who are working on different projects, along with collaborators in the clinic who can help move our findings forward,” said Dr. Lemarquis. “I think there is great potential for Tregs and amphiregulin to be used therapeutically in patients receiving cancer therapies to ameliorate immune function.”
In addition to City of Hope scientists, the Immunity paper “Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following thymic damage” included authors from Memorial Sloan Kettering Cancer Center, the University of Gothenburg in Sweden, Bambino Gesù Children’s Hospital in Rome, New York-Presbyterian Morgan Stanley Children's Hospital, the University of Washington, Fred Hutchinson Cancer Center in Seattle and Weill Cornell Medical College in New York. The research was supported by funding from the National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute on Aging and DKMS.
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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 U.S. 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 top 5 in the nation for cancer care by U.S. News & World Report at its core, City of Hope brings a uniquely integrated model that 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, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.
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