Tufts researchers find immune cell link to doxorubicin-induced heart damage

There is still much to learn about how doxorubicin, a 50-year-old chemotherapy drug, causes its most worrisome side effects. Although it has saved many lives, the treatment sometimes causes heart damage that stiffens the heart and puts a subset of patients at risk for future heart failure. To better understand and potentially control such complications, researchers at Tufts University School of Medicine and Tufts Graduate School of Biomedical Sciences isolated immune cells that become overactive when patients take doxorubicin. The team’s findings appear July 17 in the journal Circulatory system research in nature.

Doxorubicin is oncologists’ top choice as a first line of defense against a variety of cancers because of its ability to tardy or stop cell division and thus tumor growth. The drug has been shown to trigger a proinflammatory response in the heart, but there is no intervention that is broadly effective in preventing this, and it’s unclear how or why this happens, so Tufts researchers are trying to close those gaps.

Their studies found elevated levels of powerful virus-killing CD8+ T cells—a type of immune cell—and their molecular attractants in the blood of well mice after they started doxorubicin. This observation was further confirmed in dozens of lymphoma patients in dogs and humans. Further work in a mouse model showed that these T cells not only traveled to the heart and interacted directly with heart tissue, but that their removal alleviated heart inflammation and fibrosis—scarring of the heart muscle caused by injury.

Our study is the first to show that a specific cell type can cause chronic inflammation in the heart after doxorubicin treatment, and the first time that T cells have been implicated in this disease. This suggests that blocking T cells from entering the heart could be a strategy for developing a drug to prevent drug-related heart damage.

Abe Bayer, first author, MD/PhD Immunology student at Tufts University

Bayer and his colleagues found that something in doxorubicin causes CD8+ T cells to become dysfunctional because they recognize something in the heart as foreign, leading to their overactivity. The reason the chemotherapy drug pulls T cells out of the blood to attack heart tissue has not yet been defined, but that will be the subject of future work.

The research team found that once inside the heart, CD8+ T cells can cause changes in the organ, leaving heart tissue scarred, heavily fibrotic, and less able to function. Their studies showed that in mice, the T cells release molecules that are meant to cause the death of cells that would normally fight viruses and other invaders, but these molecules cause fibrosis and stiffen the heart, preventing it from contracting properly.

“The goal of this work is to prevent people from dying, whether from heart disease or cancer, and that means making sure people can safely take these powerful chemotherapy drugs,” says senior author Pilar Alcaide, the Kenneth and JoAnn G. Wellner Professor in the School of Medicine. “While we don’t know what the solutions will look like, this study opens a lot of doors to potential preventive strategies that protect the heart while still allowing this drug to be effective on cancer cells.”

In addition to investigating how to block CD8+ T cells from entering the heart without affecting doxorubicin’s ability to fight cancer, the team’s future research will also look at whether molecules that attract T cells to the heart, called chemokines, can serve as biomarkers to monitor or predict heart damage, leading to more personalized and safer treatment plans for patients.

The Tufts team was able to conduct such a thorough, cross-species study because of the availability of canine and human cancer patient samples on campus, as well as at the broader Boston hospital network, most notably Beth Israel Deaconess Medical Center. Dogs experience the same side effects of doxorubicin as humans, and the researchers are working closely with co-author Cheryl London, associate dean for research and graduate education and the Anne Engen and Dusty professor of comparative oncology at the Cummings School of Veterinary Medicine at Tufts University, to apply what they learn to treating our animal companions.

“I’m really excited about this paper because it’s something completely novel in a very antique field,” Bayer says. “It’s tough to do, but I hope it inspires more people not to look at a pile of literature and not be afraid to add something to the top. Science is too complicated to say we’ve got it all figured out.”

The research described in this article was supported by the National Institutes of Health, the American Heart Association, and a Tufts Springboard grant. Full details of authors, funders, methodology, and conflicts of interest are available in the published article.

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