Findings could lead to better understanding of ischemic cardiovascular events and help the development of new treatments
Newswise — (NEW YORK, NY – October 3, 2019) –Atherosclerotic plaque, the fatty buildup in arteries that can lead to heart attack and stroke, contains an abundance of the immune cells known as T-cells, Mount Sinai researchers have shown for the first time.
T-cells are an essential part of the human immune system, helping to protect the body from infection and cancer, but they are suspected of aggravating atherosclerosis. The breakthrough findings, published in the October 7 issue of Nature Medicine, result from a deep single-cell analysis of immune cells in plaque, something that has never been done before in humans. This research can help doctors better understand how the immune system contributes to cardiovascular disease and complications. The study could also lead to development of drugs to target these cells to prevent cardiovascular events.
“This is a first study towards the ultimate goal of building a single-cell immune atlas of human atherosclerosis. By profiling individual cells in blood and atherosclerotic plaques, we found new inflammatory alterations in plaques related to cardiovascular events,” said lead investigator Chiara Giannarelli, MD, PhD, Assistant Professor of Medicine (Cardiology), and Genetics and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai. “We found that T-cells, a cell type known to fight infections and cancer, may have an unanticipated important role in driving atherosclerotic cardiovascular disease. Exploring the diversity of T-cells in human atherosclerosis may lead to new therapeutics in the future.”
Researchers studied 46 patients undergoing carotid artery surgery at The Mount Sinai Hospital (both men and women, with an average age of 72). Forty percent of the patients had recently had a stroke. Investigators analyzed atherosclerotic plaque removed during the surgery and the patients’ blood immune cells. The team used a combination of cutting-edge technologies (called CyTOF, single-cell RNA sequencing, and CITE-seq) to get an in-depth look at the individual protein and gene expression of single cells. They discovered that these patients had an abundance of T-cells along with an increased infiltration of a subset of pro-inflammatory T-cells called CD4+ in patients who had suffered a recent stroke.
Surprisingly, many other subsets of T-cells, including CD8+ T cells, were infiltrating plaques in different forms: some were highly active or inflammatory, others were differentiated and highly specialized to the plaque environment, and some subsets were exhausted, which means they were progressively losing their ability to kill disease cells. Additionally, the exhausted T-cells in these plaques expressed PD-1, a protein that normally prevents T cells from killing other cells including cancer cells.
Normally, CD8+ T cells operate by recognizing and killing cancer cells or cells infected by viruses. More research is needed to identify their specific function and cell targets in atherosclerotic plaques. Ultimately, all these cell subsets and different functions may contribute to increase plaque inflammation in stroke patients, possibly putting these patients at a higher risk of future cardiac events, the researchers said.
“These findings suggest that PD-1 inhibitors, a breakthrough treatment that is used in cancer to turn T-cells against the tumor, may also activate exhausted T-cells in plaque. This could increase plaque inflammation and possibly the risk for cardiovascular events in patients,” said Dr. Giannarelli.
“This study is a perfect example of how single-cell mapping of human disease lesions can transform our understanding of disease pathophysiology,” explained co-author Miriam Merad, MD, PhD, Director of the Precision Immunology Institute, and Director of the Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai. “This study has generated a new hypothesis about disease drivers that we hope will lead to novel therapies.”
“This study shows the molecular connections linking blood and cellular make-up of the atherosclerotic plaque within the same individual and the clinical outcome,” said Michelle Olive, Ph.D., Program Officer at the National Heart, Lung, and Blood Institute Division of Cardiovascular Sciences. “This study shows that cutting edge techniques like CyTOF and other single cell technologies are useful in charting the landscape of atherosclerotic plaques.”
J Mocco, MD, MS, Vice Chair of Neurosurgery and Director of the Cerebrovascular Center for the Mount Sinai Health System, and Peter Faries, MD, Chief of Vascular Surgery for the Mount Sinai Health System, made significant contributions to this research.
This study was funded by two grants (K23HL111339 and R03HL135289) from the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI).
About Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and the South Nassau Communities Hospital is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.
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K23HL111339; R03HL135289; Nature Medicine