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 Cancer Institute 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 metroprolol 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."