As the body ages, a persistent low-grade immune response known as chronic inflammation, or “inflammaging,” gradually spreads through tissues. This process is associated with weakened immune surveillance, impaired tissue repair and a reduced ability to control cancer. Researchers at the Keck School of Medicine of USC now believe that a hormone produced by the aging thymus may be one of the biological switches linking age-related inflammation to declining cancer immunity. Their findings have prompted a new, five-year research project backed by up to $3.2 million from the National Institutes of Health.
The hormone, thymulin, is produced by the thymus, a small immune organ located behind the breastbone. The thymus is best known for supporting the development and education of T cells, the immune cells that recognize infected or abnormal cells. Its activity declines substantially with age, a process called thymic involution. According to the USC team, thymulin levels fall alongside this structural and functional decline, while inflammatory signals rise. The researchers propose that this hormonal loss may influence the immune system far beyond T-cell production, affecting the broader inflammatory environment in which cancer develops and responds to treatment.
In a study published in Nature Communications, the scientists reported that restoring thymulin reduced inflammation and improved survival in older mice with cancer. The hormone also made immunotherapy more effective in these animals. The work is significant because it moved beyond an association between an aging thymus and inflammation, identifying a causal chain in which reduced thymulin activity contributes to an inflammatory state that can accelerate cancer progression and interfere with immune-based treatment. The findings provide a possible explanation for why many older patients respond differently to immunotherapy than younger individuals.
“Scientists have traditionally viewed the aging thymus as important mainly because of its effects on one part of the immune system—T cells,” said Fumito Ito, MD, PhD, professor of surgery and immunology and immune therapeutics at the Keck School of Medicine and principal investigator of the research. “Our findings suggest its influence is much broader, helping regulate chronic inflammation in ways that affect cancer.” The new grant will allow the team to examine how thymulin communicates with immune cells and whether that communication can be converted into a treatment strategy.
The first phase of the project will focus on the molecular mechanisms behind thymulin’s anti-inflammatory effects. Researchers will study immune cells in living mice as well as human immune cells in laboratory experiments. They plan to map the signaling pathways activated by thymulin and identify the genes whose activity changes after exposure to the hormone. These experiments could reveal whether thymulin acts directly on immune cells, alters the production of inflammatory molecules or reshapes communication among several cell types. Understanding these steps will be essential for determining how the hormone might be used safely in humans.
The researchers will then investigate how thymulin changes the tumor microenvironment, the complex network of cancer cells, immune cells, blood vessels and signaling molecules surrounding a tumor. Many cancers suppress immune activity by creating an environment that prevents T cells from entering the tumor or stops them from killing malignant cells. In aged mice with breast cancer or melanoma that respond poorly to immunotherapy, the team will test whether thymulin can reverse some of these effects. A central question is whether the hormone generates new anti-cancer immune responses, strengthens immune attacks that already exist, or performs both functions.
The project will also examine thymulin’s potential against metastatic disease. Metastasis occurs when cancer cells leave the original tumor, travel through the bloodstream or lymphatic system and establish tumors in distant organs. These secondary tumors are responsible for most cancer-related deaths and are often difficult to treat with immunotherapy alone. Ito’s group will test whether thymulin can prevent metastatic tumors from forming and whether it can slow the growth of metastases that are already established. The experiments will use aged mice carrying breast cancer or melanoma, with complementary studies conducted on human cells in the laboratory.
The investigators are particularly interested in the possibility of using thymulin as an add-on treatment for older patients receiving immune checkpoint inhibitors. Drugs targeting PD-1 or PD-L1 can restore the activity of exhausted T cells, but only a portion of patients benefit. Chronic inflammation may contribute to treatment resistance by disrupting immune coordination and creating conditions that favor tumor survival. If thymulin can reduce this inflammatory interference without suppressing anti-tumor immunity, it could potentially improve responses to existing therapies. At this stage, however, the concept remains preclinical and has not been tested as a cancer treatment in patients.
Most cancer research has historically relied on young laboratory animals, even though cancer is primarily a disease of later life. Aging affects immune-cell production, metabolism, tissue structure and the chemical signals that regulate inflammation, meaning that results from young animals may not accurately predict how older patients respond. By conducting the new experiments in aged mice, the USC team hopes to model the biology of cancer and immunotherapy more realistically. “To treat diseases of aging, we need models that reflect the biology of aging,” Ito said. “Our goal is to make what we learn in the laboratory as relevant as possible to the patients most often affected by cancer.”
Subject of Research: Thymulin, age-related chronic inflammation, cancer progression, metastasis and immunotherapy response.
Web References: Keck School of Medicine of USC; USC news release on thymulin and age-related inflammation.
References: Nature Communications study by Fumito Ito and colleagues; National Institutes of Health grant 1R01CA316597-01.
Keywords: Thymulin, inflammaging, thymus, cancer immunotherapy, immunology, aging, chronic inflammation, metastasis, breast cancer, melanoma, PD-1, PD-L1, gerontology.
