NIH funds research to explore the role of thymulin in inflammaging and cancer

As we age, chronic inflammation-or "inflammaging"-increases throughout the body and weakens our ability to fight cancer. But scientists have only recently started to uncover the biological processes that drive it.

Thymulin, a hormone produced by a small organ behind the breastbone known as the thymus, keeps chronic inflammation under control, according to a Keck School of Medicine of USC study published in Nature Communications earlier this month. As we age, thymulin levels drop and inflammation rises, weakening the immune system's ability to fight cancer.

Now, the research team behind those findings has received a five-year grant of up to $3.2 million from the National Institutes of Health to further explore the role of thymulin in inflammaging and cancer, as well as its therapeutic potential.

Scientists have traditionally viewed the aging thymus as important mainly because of its effects on one part of the immune system-T cells. Our findings suggest its influence is much broader, helping regulate chronic inflammation in ways that affect cancer."

Fumito Ito, MD, PhD, professor of surgery and immunology and immune therapeutics, Keck School of Medicine and principal investigator of the study

Immunotherapy has revolutionized cancer treatment, but many patients still do not benefit-and Ito's findings may help explain why. In the new project, the researchers will explore whether thymulin can be used as an add-on treatment to help older individuals respond better to immunotherapies, including anti-PD-1 and anti-PD-L1 therapies. They will also test the hormone's potential for treating metastatic cancers. The preclinical studies will be conducted in aged mice with either breast cancer or melanoma, with additional testing done on human cells in the lab.

"By targeting one of the underlying drivers of inflammaging, we hope to help the immune system fight cancer more effectively, particularly in older individuals," said Ito, who is also vice chair of basic and translational science in the Department of Surgery.

How thymulin controls inflammation

In their Nature Communications paper, Ito and his colleagues showed that thymulin reduced inflammation, improved survival and made immunotherapy more effective in older mice with cancer. While earlier studies had linked the thymus to inflammaging, Ito's group identified thymulin as a key regulator of that process. For the first time, they also established a causal chain connecting thymulin to inflammation, cancer progression and immunotherapy response. 

The new grant provides funding to delve deeper into those findings, with three primary goals. First, the researchers will investigate the precise molecular mechanism thymulin uses to control inflammation. To understand the biological signaling pathways involved, they will study both mouse immune cells in living organisms and human immune cells in laboratory experiments. They will also identify which genes thymulin switches on and off to help control inflammation.

Next, the researchers will study how thymulin changes the immune environment inside tumors. In mice with forms of breast cancer and melanoma that do not respond well to immunotherapy, they will test whether the hormone helps the immune system mount a stronger attack against cancer. One key question: Is thymulin generating new anti-tumor immune responses, boosting an existing immune attack, or both?

Finally, Ito and his colleagues will test whether thymulin can work against metastasis, either by preventing metastatic tumors from forming or by slowing down established metastatic cancer.

Supporting older patients

Most cancers occur later in life, but much of what scientists know about cancer immunotherapy comes from studies of young animals. By working with older mice, the team hopes to better understand how aging reshapes the immune system and to develop therapies more likely to translate successfully to older patients.

"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."