Existing therapies capable of reducing stress responses may boost effectiveness of immunotherapy
- Researchers report new understanding of negative effects of chronic stress
- Beta blockers reduce stress signaling and improve anti-tumor immunity
- A Roswell Park-led clinical study based on these findings is anticipated
BUFFALO, N.Y. — While the development of therapies designed to block “checkpoints” within the immune system has been one of the most exciting and noteworthy advances in cancer research in recent years, it’s also been one of the most puzzling, leaving researchers to ask: Why don’t these new therapies work for more patients, and why is their efficacy in controlling cancerous tumors often short-lived? A research team from Roswell Park Comprehensive Cancer Center has shown that at least one answer — and an excellent opportunity for unleashing the full potential of these promising immunotherapies — may lie in the body’s “fight or flight” reaction to stressors and in drugs already widely used to control and temporarily disable this stress response.
In new preclinical research published online ahead of print in Cancer Research, a journal of the American Association for Cancer Research, a Roswell Park team led by Elizabeth Repasky, PhD, reports that beta-2 (β2) adrenergic receptors, molecules present in the cells of humans and other mammals, control the functionality of key immune cells. In response to stressors, these receptors turn on the “flight or fight” response. They generate more of the stress hormone norepinephrine, buffering normal cells from some damaging effects but also impeding the immune system’s ability to fight cancer.
The researchers pursued the implications of this novel finding with further laboratory studies, and demonstrate in this new report that the β2 adrenergic receptor, also known as ADRB2, can be pharmacologically manipulated. Beta blockers — FDA-approved therapies, such as metoprolol and propranolol, that are commonly used to treat conditions including hypertension (high blood pressure), angina, cardiac arrhythmia and anxiety — appear to be an effective means of reducing beta-2 receptor signaling and may, in the process, be repurposed to improve the efficacy of anti-PD-1 checkpoint blockade.
“Our bodies respond to certain types of stress — such as fear and anxiety, heat, cold, pain, depression and even attack by cancer cells — in the same way. We jump into ‘fight or flight’ mode, and the sympathetic nervous system dials up the release of norepinephrine,” says Dr. Repasky, the Dr. William Huebsch Professor of Immunology at Roswell Park and senior author on the new publication. “For reasons that we don’t entirely understand yet, prolonged exposure to these stressors often makes our immune cells much less effective. But we demonstrate here that beta blockers, by reducing adrenergic signaling, allow anti-tumor immune cells to become much stronger, and give immunotherapies, and in particular checkpoint inhibitors, a much better chance to work.”
Marc Ernstoff, MD, the Katherine Anne Gioia Chair of Medicine at Roswell Park, expects to soon initiate a multicenter clinical study based on these findings.
“The possibility of improving responses to checkpoint inhibitors and perhaps expanding the numbers of patients who can benefit from them by pairing them with drugs that have been broadly available for years and are generally very well tolerated is quite compelling,” says Dr. Ernstoff. “We look forward to determining whether an approach that combines anti-PD-1 therapy with a beta blocker will be as effective as these intriguing preclinical studies suggest.”
This research was supported by a Peter T. Rowley Breast Cancer Research Grant from the New York State Department of Health and by grants from the Harry J. Lloyd Charitable Trust, Roswell Park Alliance Foundation, Breast Cancer Coalition of Rochester and National Cancer Institute (project nos. T32CA085183, R01CA140622 and P30CA016056). The study, “β-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy,” is available at cancerres.aacrjournals.org.
The mission of Roswell Park Comprehensive Cancer Center is to understand, prevent and cure cancer. Founded in 1898, Roswell Park is one of the first cancer centers in the country to be named a National Cancer Institute-designated comprehensive cancer center and remains the only facility with this designation in Upstate New York. The Institute is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers; maintains affiliate sites; and is a partner in national and international collaborative programs. For more information, visit www.roswellpark.org, call 1-877-ASK-Roswell Park (1-866-559-4838) or email AskRoswell@Roswellpark.org. Follow Roswell Park on Facebook and Twitter.
Annie Deck-Miller, Senior Media Relations Manager