Impaired blood flow alters immunity and fuels tumor progression

Cutting off blood flow can prematurely age the bone marrow, weakening the immune system's ability to fight cancer, according to a new study from NYU Langone Health.

Published online August 19 in JACC-CardioOncology, the study showed that peripheral ischemia–restricted blood flow in the arteries in the legs–caused breast tumors in mice to grow at double the rate seen in mice without restricted flow. These findings build on a 2020 study from the same team that found ischemia during a heart attack to have the same effect.

Ischemia occurs when fatty deposits, such as cholesterol, accumulate in artery walls, leading to inflammation and clotting that restrict the flow of oxygen-rich blood. When this happens in the legs, it causes peripheral artery disease, which affects millions of Americans, and can increase the risk of heart attack or stroke. 

Our study shows that impaired blood flow drives cancer growth regardless of where it happens in the body. This link between peripheral artery disease and breast cancer growth underscores the critical importance of addressing metabolic and vascular risk factors as part of a comprehensive cancer treatment strategy." 

Kathryn J. Moore, PhD, corresponding author, the Jean and David Blechman Professor of Cardiology in the Department of Medicine, Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine

Importantly, the research team found that restricted blood flow triggers a shift toward immune cell populations that cannot efficiently fight infections and cancer, mirroring changes seen with aging. 

Systemic skewing

To examine the mechanisms behind the link between cardiovascular disease and cancer growth, the study authors developed a mouse model with breast tumors and induced temporary ischemia in one hind limb. The team then compared cancer growth in mice with and without impaired blood flow.

Their findings build on the nature of the immune system, which evolved to attack invading bacteria and viruses, and under normal conditions, to detect and eliminate cancer cells. These protective functions rely on stem cell reserves in the bone marrow, which can be activated as needed to produce key white blood cell populations throughout life.

Normally, the immune system responds to injury or infection by ramping up inflammation to eliminate threats, then scaling back to avoid harm to healthy tissue. This balance is maintained by a mix of immune cells that either activate or suppress inflammation. The researchers found that reduced blood flow disrupts this equilibrium. It reprograms stem cells in the bone marrow to favor the production of "myeloid" immune cells (monocytes, macrophages, neutrophils) that dampen immune responses, while reducing output of lymphocytes like T cells that help to mount strong anti-tumor responses.

The local environment within tumors showed a similar shift, accumulating more immune-suppressive cells– including Ly6Chi monocytes, M2-like F4/80+ MHCIIlo macrophages, and regulatory T cells – that shield cancer from immune attack. 

Further experiments showed that these immune changes were long-lasting. Ischemia not only altered the expression of hundreds of genes, shifting immune cells into a more cancer-tolerant state, but also reorganized the structure of chromatin–the protein scaffolding that controls access to DNA–making it harder for immune cells to activate genes involved in fighting cancer.

"Our results reveal a direct mechanism by which ischemia drives cancer growth, reprogramming stem cells in ways that resemble aging and promote immune tolerance," says first author Alexandra Newman, PhD, a postdoctoral scholar in Dr. Moore's lab. "These findings open the door to new strategies in cancer prevention and treatment, like earlier cancer screening for patients with peripheral artery disease and using inflammation-modulating therapies to counter these effects."

Moving forward, the research team hopes to help design clinical studies that evaluate whether existing inflammation-targeted therapies can counter post-ischemic changes driving tumor growth.

Along with Drs. Newman and Moore, study authors from the Cardiovascular Research Center and the Leon H. Charney Division of Cardiology, both within the Department of Medicine at the NYU Grossman School of Medicine, were Jose Gabriel Barcia Duran, Richard Von Itter, Jessie Dalman, Brian Lim, Morgane Gourvest, Tarik Zahr, Kristin Wang, Tracy Zhang, Noah Albarracin, Whitney Rubin, Fazli K. Bozal, Chiara Giannarelli, Michael Gildea, and Coen van Solingen. Also an author was Kory Lavine of the Department of Pathology and Immunology at Washington University School of Medicine, Saint Louis.